Mixed lineage kinase inhibitors and method of treatments

ABSTRACT

Provided herein are imidazopyridine compounds having an inhibitory effect on mixed lineage kinases (MLKs), methods of their synthesis, and methods of their therapeutic. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 14/201,673, filed Mar.7, 2014, which claims the benefit of priority Application Ser. No.61/774,211, filed on Mar. 7, 2013, all of which is expresslyincorporated herein by reference in their entireties.

GOVERNMENT SUPPORT

This work was supported in part by Small Business Innovation ResearchGrants 1R43MH093270-01 and 2R44MH093270-02 from the National Institutesof Mental Health of the National Institutes of Health. The governmenthas certain rights in the invention.

FIELD OF THE INVENTION

The present disclosure relates to imidazopyridine compounds having aninhibitory effect on mixed lineage kinases (MLKs), including familymembers in groups (e.g., MLK-1, MLK-2, MLK-3), and their synthesis. Thedisclosure also relates to pharmaceutical compositions comprising thecompounds disclosed herein, and methods for therapeutic and/orprophylactic use of these compounds. In a particular aspect, thedisclosure relates to compounds that inhibit the MLK-3 family.

INTRODUCTION

Mixed lineage kinases (MLKs) are MAPK kinase kinases that targetactivated c-Jun N-terminal kinases (JNK) and p38 MAPK for activation inresponse to diverse stimuli associated with cell stress. As a result,MLKs regulate a broad range of cellular processes. MLK-3 is the mostwidely expressed MLK family and is present in neurons.

JNKs are major control nodes in mammalian apoptotic cell death pathways.For example, GTP-bound forms of the G proteins Rac1 and Cdc42 promoteautophosphorylation and activation of MLKs which, in turn, phosphorylateand activate mitogen-activated protein kinase kinases 4 and 7 (MKK₄ orMKK₇), which ultimately phosphorylate and activate JNKs. MLK-3 is widelydistributed and up-regulated in inflammatory states in various organsincluding the brain and heart. The first generation, pan-MLK inhibitorCEP-1347 has been shown to protect primary rat hippocampal neurons aswell as dorsal root ganglion neurons from the otherwise lethal effectsof exposure to HIV-1 gp120. (Bodner, A., Toth, P. T. & Miller, R. J.Activation of c-Jun N-terminal kinase mediates gp120IIIB- and nucleosideanalogue-induced sensory neuron toxicity. Exp Neurol 188, 246-253(2004); Bodner, A. et al. Mixed lineage kinase 3 mediatesgp120IIIB-induced neurotoxicity. J Neurochem 82, 1424-1434 (2002)).Neurotoxic HIV gene products Tat and gp120 induce autophosphorylationand activation of MLK-3 in primary rat neurons and this process can beabolished by the addition of CEP-1347. CEP-1347 enhances survival ofboth rat and human neurons and inhibited the activation of humanmonocytes after exposure to Tat and gp120. Furthermore, overexpressionof wild-type MLK-3 leads to the induction of neuronal death, whereasexpression of a dominant negative MLK-3 mutant protected neurons fromthe toxic effects of Tat. CEP-1347 is neuroprotective in an in vivomodel of HIV-1 infection, reversing microglial activation and restoringnormal synaptic architecture, as well as restoring macrophage secretoryprofiles to a trophic vs. toxic phenotype in response to HIV-1infection. (Eggert, D. et al. Neuroprotective activities of CEP-1347 inmodels of neuroAIDS. J Immunol 184, 746-756 (2010)). Collectively, thesestudies suggest that MLK-3 activity is increased by HIV-1 neurotoxins,resulting in downstream signaling events that trigger neuronal death anddamage, along with monocyte activation (accompanied by release ofinflammatory cytokines). Unfortunately CEP-1347, a close analog ofstaurosporine, is non-specific for MLK-3, and is a large molecule whereno evidence has been published showing that it penetrates the CNS.Pharmacokinetic studies in mice have demonstrated poor CNS penetrationfor CEP-1347. (Goodfellow et al, Discovery, synthesis, andcharacterization of an orally bioavailable, brain penetrant inhibitor ofmixed lineage kinase 3, J Med Chem 56 8032-48 (2013). Further,development of CEP-1347 was halted for unknown reasons.

The central nervous system (CNS) can be infected and injured by HIV-1,leading to the development of HIV-Associated Neurocognitive Disorders(HAND). Recent estimates of the prevalence of HAND suggest that over 50%of the population living with AIDS is affected. Because combinationantiretroviral therapy (cART), even in CNS penetrating forms, has notaltered the prevalence of HAND (Heaton, R. et al. HIV-associatedNeurocognitive Impairment Remains Prevalent in the Era of CombinationART: The CHARTER Study. 16th Conference on Retroviruses andOpportunistic Infections; 2009), new therapeutic strategies forcounteracting the effects of HIV infection in the CNS are needed.Preliminary studies have shown that inhibition of key signaling kinasesis likely one of the best strategies for affecting HAND-relatedinflammatory and cellular injury cascades. Sui, Z. et al. Inhibition ofmixed lineage kinase 3 prevents HIV-1 Tat-mediated neurotoxicity andmonocyte activation. J Immunol 177, 702-711 (2006); Dewhurst, S.,Maggirwar, S. B., Schifitto, G., Gendelman, H. E. & Gelbard, H. A.Glycogen synthase kinase 3 beta (GSK-3 beta) as a therapeutic target inneuroAIDS. J Neuroimmune Pharmacol 2, 93-96 (2007).

MLK-3 also modulates neuroinflammation through effects on cytokineproduction by microglia and brain macrophages. In particular,CEP-1347-mediated inhibition of MLK-3 results in a significant decreasein Tat-stimulated release of tumor necrosis factor alpha (TNF-α) andinterleukin (IL)-6 by macrophage and microglia. (Sui, Z., Kovacs, A. D.& Maggirwar, S. B. Recruitment of active glycogen synthase kinase-3 intoneuronal lipid rafts. Biochem Biophys Res Commun 345, 1643-1648 (2006)).Similar results have been demonstrated in macrophages with CNS penetrantMLK-3 inhibitor URMC-099. (Goodfellow et al, 2013.) TNF-α mediates asignificant part of Tat-mediated toxicity in models of HAND, andinhibition of this pathway by CEP-1347 may account for the reduction inneuroinflammation observed in an in vivo model for HAND. Recently a thepotent and brain penetrant MLK3 inhibitor, URMC-099 has demonstrated invivo efficacy for preservation of normal synaptic architecture andreversal of neuroinflammation following CNS exposure to HIV-1 Tat.(Marker et al, The new small-molecule mixed-lineage kinase 3 inhibitorURMC-099 is neuroprotective and anti-inflammatory in models of humanimmunodeficiency virus-associated neurocognitive disorders, J Neurosci24 9998-10010 (2013).) URMC-099 however is not a selective inhibitor ofMLK3. In order to limit off target activity there is a need to identifyand develop compounds with greater specificity for MLK3.

Previously it has been shown that blockade of the MLK-3 pathway mayinterfere with the neurotoxic effect of beta amyloid oligomers. (Xu Y,Hou X Y, Liu Y, Zong Y Y, Different protection of K252a andN-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuronapoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades. JNeurosci Res. 2009 March; 87(4):918-27).) Inhibition of the C-jun/JNKpathway blocks hyperphosphorylation of tau in cultured hippocampalneurons. (J. Neurosci. 2009 Jul. 15; 29(28):9078-89). Consequently,MLK-3 inhibitors may be of value in the treatment of Alzheimer diseaseand other neurodegenerative diseases involving the C-jun/JNK pathway.

Recent evidence also suggests that acute and temporary blockade of thec-jun/JNK pathway at early stages of stroke may improve outcomes. (J.Neurosci. 2012 Jun. 13; 32(24):8112-5).

Attenuation of microglial activation via MLK-3 inhibition protectshippocampal synapses in experimental autoimmune encephalomyelitis modelsof multiple sclerosis. MLK-3 inhibitors may be useful for the treatmentof multiple sclerosis and other inflammatory neurological diseases.(Bellizzi M and Gelbard, H. Neurology Apr. 25, 2012; 78(MeetingAbstracts 1): P05.112.)

Small molecule inhibition of MLK-3 attenuates cardiac fibroblastactivation and pathologic cardiac remodeling. (Martin, M. L., Dewhurst,S., Gelbard, H. A., Goodfellow, V., Blaxall, B. C.; Circulation Research111 (4) A88 (2012)). Consequently, MLK-3 inhibitors may be useful forthe treatment of heart failure.

MLK-3 blockade inhibits stellate cell proliferation in the liver andpancreas and may be useful for treatment of cirhotic diseases of theseorgans. (Cancer Research 59 2195-2202(1999)). MLK3 blockade may serve asa useful treatment for steatohepatitis. (Ibrahim S H, Gores G J, HirsovaP, Kirby M, Miles L, Jaeschke A, Kohli R. Mixed lineage kinase 3deficient mice are protected against the high fat high carbohydratediet-induced steatohepatitis. (Liver Int. 2013 Oct. 6. PMID:24256559)

Inhibition of MLK-3 may also be useful for the treatment of variouscancers such as cancers of the pancreas and breast. (Cancer Growth andMetastasis 2010:3 1-9). MLK-3 regulates the proliferation of some tumorcell types, including human schwannoma and meningioma cells and breastcancer cells also over-express MLK-3 (Chen J, Miller E M, Gallo K A.Oncogene. 2010; 29(31):4399-411). RNA-mediated knockdown of MLK-3inhibits growth and lymph node metastasis of human breast cancer cellsin a mouse xenograft model. (Oncogene. 2011 PMC: 3297722)). MLK-3inhibitors may be efficacious in treating metastasized breast tumors andcompounds which are highly CNS penetrant may be especially useful intreating metastasized tumors in the brain associated with breast cancer.

Both HAND and Parkinson's Dementia have similar underlying pathologyinvolving dopaminergic pathways and synaptodendritic damage. Destructionof striatal dopaminergic neurons results in a significant loss ofdendritic spines on medium spiny projection neurons (MSNs) inParkinson's disease. MSNs are the main output neurons of the striatum.MSNs are the primary synaptic target of both nigrostriatal dopaminergicand cortico-striatal glutamatergic afferent neurons. Dendritic spinesare critical sites for synaptic integration. For a treatment forParkinson's Disease to be effective, dopaminergic neurotransmission mustbe normalized and MSN spine loss and dendritic atrophy need to bereversed. The MLK3 inhibitor, CEP-1347, was developed as a clinicalcandidate for Parkinson's Disease. CEP-1347 exhibited striking positiveactivity in numerous in vitro and in vivo models for PD includingneuroprotection using methamphetamine-exposed humanmesencephalic-derived neurons. CEP-1347 prevented the induction ofneuronal cell death, motor deficits and neuronal degeneration in theMPTP model of Parkinsonism in mice and monkeys. However, the compoundfailed to exhibit efficacy in human trials for preventing thedevelopment of disease progression in early stage Parkinson's Disease.(PRECEPT GROUP, Mixed lineage kinase inhibitor CEP-1347 fails to delaydisability in early Parkinson disease, Neurology 15 1480-90 (2007).) Theonly available pharmacokinetic data for CEP-1347 shows wide patientvariability of plasma levels for the drug in patients, suggestingmetabolic or induction issues. (Ma et al, J Neurovirol 19 254-60 (2013.)Pharmacokinetic studies in mice have shown very poor blood brain barrierpenetration for CEP-1347 (Goodfellow et al, 2013). A compound withsubstantially increased ability to maintain high brain concentrationlevels may offer better potential for treating Parkinson's Disease.

Accordingly, there still is a great need to develop potent inhibitors ofMLKs, including groups MLK-3, that are useful in treating variousconditions associated with MLK activation.

SUMMARY OF THE INVENTION

Disclosed herein are compounds having an inhibitory effect on MLKs,including the families MLK-1, MLK-2, and MLK-3. Also provided arepharmaceutical compositions thereof, methods of preparation thereof, andmethods of use thereof, such as in treatment of a malcondition mediatedby MLKs receptor activation, or when modulation or potentiation of MLK-3receptor is medically indicated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows images of E18 primary hippocampal neurons which were platedin microfluidic chambers before and after introduction of BV-2microglial cells treated with HIV-1 Tat (1 ug/mL) and test inhibitorcompounds (100 nM). Arrows show examples of continued axonogenesis inthe presence of Tat-activated microglia, facilitated by a compound ofthe present disclosure (Compound 68).

FIG. 2 is a graph illustrating the quantification of axon elimination inthe presence of HIV tat and certain inhibitors including compounds ofthe present disclosure.

FIG. 3 is a graph illustrating the quantification of axon length in thepresence of HIV tat and certain inhibitors including compounds of thepresent disclosure.

FIG. 4 is a graph illustrating dose-dependent neuroprotection from NMDAexcitotoxic activation of matrix metalloproteinases with cleavage ofintercellular adhesion molecule type 5 (ICAM-5).

FIG. 5 is a graph illustrating the inhibition of synaptodendriticbeading induced by N-methyl-D-aspartate (NMDA) receptor.

DETAILED DESCRIPTION OF THE INVENTION

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula I

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

J has a structure of

where J (i.e., any carbon atom on J) can be optionally substituted withup to four R₁₀, each R₁₀ can be independently selected from the groupconsisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy —OH, and—OCOR₆;

X can be NR₁₂ or S;

X₁, X₂, X₃, and X₄ can be H or N and wherein no more than one of X₁, X₂,X₃, and X₄ is N;

Y can be —W—(CH₂)_(n)—R₁,

W can be null, phenylene, or —NR₆-phenylene, where the NR₆ is attachedto the imidazopyridazine core structure of Formula I;

R₁ can be —NR₂R₃, or piperazinyl, where the nitrogen atom of thepiperazinyl can be optionally substituted with alkyl or alkoxy;

R₂ can be H or alkyl; R₃ can be selected from the group consisting ofC₂-C₁₀ alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, whereany atom of R₃ can be optionally substituted with one or more R₇; or R₂and R₃ taken together with the N atom to which they are attached form a3- to 7-membered heterocyclic ring optionally substituted with R₈;

R₄ can be H or alkyl;

R₅ can be H, alkyl, or NHR₉;

R₆ can be H or alkyl;

each R₇ can be independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH;

R₈ can be alkoxy, hydroxyalkyl, or COOR₁₁;

R₉ can be H, alkyl, or cycloalkyl;

R₁₁ can be H, or alkyl;

R₁₂ can be H, or alkyl;

n can be 0 or 1;

m can be 1, 2, or 3; and

p can be 1, 2, or 3;

with the proviso that if J is an unsubstituted benzothiophene, then R₃is either aryl or heteroaryl, where any atom of R₃ can be optionallysubstituted with one or more R₇.

In certain of such embodiments, the disclosure provides compounds whereJ can be selected from the group consisting of

In certain embodiments, J can be

wherein each R₁₀ can be independently selected from the group consistingof F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and—OCOCH₃; and k can be 0, 1, 2, or 3.

In certain embodiments, J can be

wherein i can be 0 or 1, 2.

In certain embodiments, wherein J can be

In certain embodiments, J can be

wherein each R₁₀ can be independently selected from the group consistingof F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and—OCOCH₃; and k can be 0, 1, 2, or 3. In certain embodiments, R₁₀ can be—OH or —OCOCH₃. In one embodiment, each of X₁, X₂, X₃, and X₄ can be CH.In one embodiment, X₁ can be N, and each of X₂, X₃, and X₄ can be CH. Inone embodiment, X₂ can be N, and each of X₁, X₃, and X₄ can be CH. Inone embodiment, X₃ can be N, and each of X₁, X₂, and X₄ can be CH. Inone embodiment, X₄ can be N, and each of X₁, X₂, and X₃ can be CH.

In certain embodiments, J can be

wherein each R₁₀ can be independently selected from the group consistingof F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and—OCOCH₃; and k can be 0, 1, 2, or 3.

In certain embodiments, J is

wherein k can be 0, 1, or 2.

In certain embodiments, J is

wherein R₁₀ can be selected from the group consisting of F, Cl, —OH,methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH₃.

In certain embodiments, the disclosure provides compounds where Y can be—W—(CH₂)_(n)—R₁. In certain embodiments, Y can be R₁. In certainembodiments, R₁ can be —NR₂R₃.

In certain embodiments, R₂ can be H.

In certain embodiments, R₃ can be C₂-C₁₀ alkyl, aryl, and cycloalkyl,where any atom of R₃ can be optionally substituted with one or more R₇,where any atom of R₃ can be optionally substituted with one or more R₇.In certain embodiments, R₃ can be phenyl optionally substituted with oneor more R₇, wherein each R₇ can be independently selected from the groupconsisting of hydroxyl, methoxy, —COOH, —O—(CH₂)_(m)—OH,cyclopropylmethoxy, cyclopentylmethoxy, and isopropyl. In certainembodiments, each R₇ can be independently selected from the groupconsisting of methoxy, —COOH, and —O—(CH₂)₃—OH.

In certain embodiments, R₃ can be C₂-C₁₀ alkyl or cycloalkyl, where anyatom of R₃ can be optionally substituted with one or more R₇.

In certain embodiments, R₃ can be aryl. In further embodiments, R₃ canbe phenyl. In certain embodiments, R₃ can be phenyl substituted with oneor more R₇, where each R₇ can be independently selected from the groupconsisting of hydroxyl, methoxy, —COOH, —O—(CH₂)_(m)—OH,cyclopropylmethoxy, cyclopentylmethoxy, and isopropyl. In furtherembodiments, each R₇ can be independently selected from the groupconsisting of methoxy, —COOH, and —O—(CH₂)₃—OH. In certain embodiments,R₃ can be phenyl substituted with at least one R₇ and wherein the atleast one R₇ can be methoxy. In certain embodiments, the at least onemethoxy substituent can be substituted at the ortho position of thephenyl. In certain embodiments, the at least one methoxy substituent canbe substituted at the meta position of the phenyl.

In certain embodiments, R₃ can be 3,4-dimethoxyphenyl. In certainembodiments, R₃ can be further substituted with —COOH or—O—(CH₂)_(m)—OH. In certain embodiments, R₃ can be further substitutedwith —O—(CH₂)₃—OH. In certain embodiments, R₃ can be phenyl substitutedwith at least one R₇. In certain of such embodiments, R₇ can be —COOH.In further of such embodiment, one of the at least one —COOH substituentof the phenyl can be at the meta position of the phenyl.

In certain embodiments, R₃ can be cycloalkyl. In certain of suchembodiments, the cyclohexyl can be substituted with one or more R₇,where each R₇ can be independently selected from the group consisting ofalkyl, —OH, hydroxyalkyl, and alkoxy. In certain embodiments, the one ormore R₇ can be each independently selected from the group consisting ofmethyl, —OH, hydroxymethyl, and methoxy. In certain embodiments, thecyclohexyl can be substituted with one R₇ at the 3-position of thecyclohexyl. In certain embodiments, the cyclohexyl can be substitutedwith one R₇ at the 4-position of the cyclohexyl. In certain embodiments,the cyclohexyl can be disubstituted with two R₇ at the 4-position of thecyclohexyl.

In certain embodiments, the substituted cyclohexyl can be in the form ofa pure diastereomer and/or enantiomer, as a racemate or as anon-equimolar or equimolar blend of the diastereomers and/orenantiomers.

In certain embodiments, R₃ can be heteroaryl.

In certain embodiments, R₃ can be pyridinyl. In certain of suchembodiments, R₃ can be pyridinyl substituted with oxo or methoxy.

In certain embodiments, R₂ and R₃ taken together with the N atom towhich they are attached form a 3- to 7-membered heterocyclic ringoptionally substituted with R₈. In certain of such embodiments, theheterocyclic ring can be a 5- or 6-membered heterocyclic ring. Incertain embodiments, R₈ is —COOCH₃, or hydoxymethyl.

In certain embodiments, W can be 1,3-phenylene or 1,4-phenylene. Incertain of such embodiments, n can be 0 or 1. In certain embodiments, R₁can be piperazinyl. In certain of such embodiments, the nitrogen atom ofthe piperazinyl can be substituted with methyl.

In certain embodiments, W can be —NR₆-phenylene. In certain of suchembodiments, the phenylene group can be 1,3-phenylene or 1,4-phenylene.In certain of such embodiments, n can be 0 or 1. In certain embodiments,R₁ can be piperazinyl. In certain of such embodiments, the nitrogen atomof the piperazinyl can be substituted with methyl.

In certain embodiments, Y can be

In certain embodiments, R₄ can be H. In other embodiments, R₄ can bealkyl, such as, lower alkyl including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, etc.

In certain embodiments, R₅ can be H.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula II

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

each R₁₀ can be independently selected from the group consisting ofhalo, alkyl, alkoxy, —OH, and —OCOR₆;

each R₇ can be independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH;

k can be 0, 1, 2, or 3; and

q can be 0, 1, 2, or 3.

In certain embodiments, each R₇ can be independently selected from thegroup consisting of methoxy, —COOH, and —O—(CH₂)₃—OH.

In certain embodiments, wherein q can be 1, 2, or 3 and at least one ofR₇ can be methoxy.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula III

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

each R₁₀ can be independently selected from the group consisting ofhalo, alkyl, alkoxy, —OH, and —OCOR₆;

each R₇ can be independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH;

k can be 0, 1, 2, or 3; and

q can be 0, 1, 2, or 3.

In certain embodiments, each R₇ can be independently selected from thegroup consisting of methoxy, —COOH, and —O—(CH₂)₃—OH.

In certain embodiments, q can be 1, 2, or 3 and at least one of R₇ canbe methoxy.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula IV

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

X can be NH or S;

each R₁₀ can be independently selected from the group consisting ofhalo, alkyl, alkoxy, —OH, and —OCOR₆; and

k can be 0, 1, 2, or 3.

In further embodiments, the present disclosure provides a compoundhaving the structure of Formula IV-A

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof.

In certain embodiments, X can be NH. In certain embodiments, X can be S.In certain embodiments, k can be 1. In certain embodiments, R₁₀ can bealkoxy. In further embodiments, R₁₀ can be methoxy.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula V

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

each R₇ can be independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH;

q can be 1, 2, or 3; and

each X₁, X₂, X₃, and X₄ can be independently H or N and wherein no morethan one of X₁, X₂, X₃, and X₄ is N.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula VI

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

R₃ can be selected from the group consisting of C₂-C₁₀ alkyl, aryl, andcycloalkyl; and

each X₁, X₂, X₃, and X₄ can be independently H or N and wherein no morethan one of X₁, X₂, X₃, and X₄ is N.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula VII

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

each R₇ can be independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH;

q can be 1, 2, or 3;

each R₁₀ can be independently selected from the group consisting of F,Cl, —OH, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH₃; and

k can be 0, 1, 2, or 3.

Certain embodiments of the present disclosure provides a compound havingthe structure of Formula VIII

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, whereinR₃ can be selected from the group consisting of C₂-C₁₀ alkyl, aryl, andcycloalkyl;

each R₁₀ can be independently selected from the group consisting of F,Cl, —OH, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH₃; and

k can be 0, 1, 2, or 3.

Certain embodiments of the present invention provide pharmaceuticalcompositions including a compound of the invention, and a pharmaceuticalcarrier, excipient or diluent. In this aspect of the invention, thepharmaceutical composition can comprise one or more of the compoundsdescribed herein.

In certain embodiments, the disclosure provides one or more of thefollowing compounds 3-9, 11-50, 52-102, 104, 107, 110-112, 114, 115,118, 119-127, 129-132, 134-143, 148-150, 158-163, 166-221, or anypharmaceutically acceptable salt, ester, prodrug, homolog, tautomer,steroisomer, isotope, hydrate, or solvate thereof. In certain of suchembodiments, the disclosure provides a compound selected from compounds3-5, 67, 68, 87, 169, 170, 175, 177, 206, 213, 215-216, and 218 or anypharmaceutically acceptable salt, ester, prodrug, homolog, tautomer,steroisomer, isotope, or hydrate, or solvate thereof.

In certain embodiments, a pharmaceutical composition comprising acompound having the structure of Formula I can be provided:

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein

J has a structure of

where J can be optionally substituted with up to four R₁₀, each R₁₀ canbe independently selected from the group consisting of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR₆;

X can be N R₁₂ or S;

each X₁, X₂, X₃, and X₄ can be independently CH or N and wherein no morethan one of X₁, X₂, X₃, and X₄ is N;

Y can be —W—(CH₂)n-R₁,

W can be null, phenylene, or —NR₆-phenylene, where the NR₆ is attachedto the imidazopyridazine core structure of Formula I;

R₁ can be —NR₂R₃, or piperazinyl, where the nitrogen atom of thepiperazinyl can be optionally substituted with alkyl or alkoxy;

R₂ can be H or alkyl; R₃ can be selected from the group consisting ofC₂-C₁₀ alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, whereany atom of R₃ can be optionally substituted with one or more R₇; or R₂and R₃ taken together with the N atom to which they are attached form a3- to 7-membered heterocyclic ring optionally substituted with R₈;

R₄ can be H or alkyl;

R₅ can be H, alkyl, or NHR₉;

R₆ can be H or alkyl;

each R₇ can be independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH;

R₈ can be alkoxy, hydroxyalkyl, or COOR₁₁;

R₉ can be H, alkyl, or cycloalkyl;

R₁₁ can be H, or alkyl;

R₁₂ can be H, or alkyl;

n can be 0 or 1;

m can be 1, 2, or 3;

p can be 1, 2, or 3; and

together with at least one pharmaceutically acceptable carrier, diluentor excipient.

In certain embodiments, a pharmaceutical composition comprising acompound of Formula II, III, IV IV-A, V, VI, VII or VIII, or anypharmaceutically acceptable salt, ester, prodrug, homolog, tautomer,steroisomer, isotope, or hydrate, or solvate thereof, together with atleast one pharmaceutically acceptable carrier, diluent or excipient isprovided.

In other embodiments, a pharmaceutical composition comprising a compoundof Formula II, III, IV IV-A, V, VI, VII or VIII or any pharmaceuticallyacceptable salt, ester, prodrug, homolog, tautomer, steroisomer,isotope, or hydrate, or solvate thereof, and a second medicament isprovided.

In certain embodiments, a pharmaceutical composition comprising acompound of the invention disclosed herein, together with at least onepharmaceutically acceptable carrier, diluent or excipient is provided.The particular carrier employed in these pharmaceutical compositions mayvary depending upon the type of administration desired (e.g.,intravenous, oral, topical, suppository, or parenteral).

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for example,as intermediates in the synthesis of Formula I, II, III, IV IV-A, V, VI,VII or VIII compounds, for example in their purification byrecrystallization. All of these salts may be prepared by conventionalmeans from the corresponding compound according to Formula I, II, III,IV IV-A, V, VI, VII or VIII by reacting, for example, the appropriateacid or base with the compound according to Formula I, II, III, IV IV-A,V, VI, VII or VIII. The term “pharmaceutically acceptable salts” refersto nontoxic inorganic or organic acid and/or base addition salts, see,for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J.Pharm., 33, 201-217, incorporated by reference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as utility in processes ofsynthesis, purification or formulation of compounds of the invention.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patients' body, such as enzymes,to the active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.

In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like can be employed.

As set forth herein, compounds of the invention include stereoisomers,tautomers, solvates, hydrates, isotopes, esters, salts includingpharmaceutically acceptable salts, and mixtures thereof. Compositionscontaining a compound of the invention can be prepared by conventionaltechniques, e.g., as described in Remington: The Science and Practice ofPharmacy, 19th Ed., 1995, incorporated by reference herein. Thecompositions can appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example, contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substances,preserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid solubility or serveas preservatives can also be included. Furthermore, injectablesuspensions can also be prepared, in which case appropriate liquidcarriers, suspending agents and the like can be employed.

If a solid carrier is used for oral administration, the preparation canbe tabletted, placed in a hard gelatin capsule, in powder or pellet formor it can be in the form of a troche or lozenge, for example. If aliquid carrier is used, the preparation can be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution or the like.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials, such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention in powder form or dissolved or suspended in a liquid carrier,preferably an aqueous carrier, for aerosol application. The carrier cancontain additives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives, such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

An embodiment of the invention also encompasses prodrugs of a compoundof the invention which on administration undergo chemical conversion bymetabolic or other physiological processes before becoming activepharmacological substances. Conversion by metabolic or otherphysiological processes includes without limitation enzymatic (e.g,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,Bundgaard, H., Ed., Elsevier, 1985.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In certain embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

The expression “effective amount,” when used to describe use of acompound of the invention in providing therapy to a patient sufferingfrom a disorder or malcondition mediated by MLK (including MLK-1, MLK-2,and MLK-3), refers to the amount of a compound of the invention that iseffective to inhibit the activity of MLK. Similarly, as used herein, an“effective amount” or a “therapeutically effective amount” of a compoundof the invention refers to an amount of the compound that alleviates, inwhole or in part, symptoms associated with the disorder or condition, orhalts or slows further progression or worsening of those symptoms, orprevents or provides prophylaxis for the disorder or condition. Inparticular, a “therapeutically effective amount” refers to an amounteffective, at dosages and for periods of time necessary, to achieve thedesired therapeutic result by acting as an inhibitor of MLK activity. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects. For example, in the context oftreating a malcondition mediated by MLK, a therapeutically effectiveamount of an MLK inhibitor of the invention is an amount sufficient tocontrol the malcondition, to mitigate the progress of the malcondition,or to relieve the symptoms of the malcondition. Examples ofmalconditions that can be so treated include, but are not limited to,diabetes mellitus, hyperglycemia, retinopathy, nephropathy, neuropathy,ulcers, micro- and macroangiopathies, gout and diabetic foot disease,insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension,hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure,atherosclerosis, peripheral inflammation, cancer, hepatitis, HIVasscociated neurocognitive disorders, HIV associated neuropathy,Alzheimer disease, Parkinson's disease, Multiple Sclerosis, and otherneurodegenerative diseases, cirrhotic diseases in liver or pancreas, andthe like.

As used herein, the term “medicament” refers to any substance orcombination of substances that has a beneficial and/or therapeuticeffect.

As used herein, the term “subject” (as in the subject of the treatment)means both mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Treating” or “treatment” refers to an alleviation of symptomsassociated with a disorder or disease, or inhibition of furtherprogression or worsening of those symptoms, or prevention or prophylaxisof the disease or disorder.

A “MLK-mediated disease” refers to a disease state which may be relievedby inhibiting MLK activity, where MLK signaling is involved in diseasepathology. Examples of MLK-mediated disorders include, stroke, diabetesmellitus, hyperglycemia, retinopathy, nephropathy, neuropathy, ulcers,micro- and macroangiopathies, gout and diabetic foot disease, insulinresistance, metabolic syndrome, hyperinsulinemia, hypertension,hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure,atherosclerosis, peripheral inflammation, cancer, hepatitis, HIVassociated neurocognitive disorders, HIV associated neuropathy,Alzheimer disease, Parkinson's disease, Multiple Sclerosis, and otherneurodegenerative diseases, cirrhotic diseases in liver or pancreas, andthe like.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [R—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-propenyl, 2-methylpropenyl, butenyl, isobutenyl, 1,4-butadienyl,isoprenyl, vinyl, and the like. Unless otherwise specified, the term“alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

Cycloalkoxy groups are alkyoxy groups forming a ring structure, whichcan be substituted or unsubstituted, wherein the ring is eithercompletely saturated, partially unsaturated, or fully unsaturated,wherein if there is unsaturation, the conjugation of the pi-electrons inthe ring do not give rise to aromaticity. The term “cycloalkoxy”embraces saturated oxy-containing carbocyclic radicals and, unlessotherwise specified, a cycloalkoxy radical typically has from 3 to 8carbon atoms. When a cycloalkoxy radical carries two or moresubstituents, the substituents may be the same or different. Examples ofsuch cycloalkyoxy groups include cyclopropoxy, cyclobutoxy,cyclopentoxy, cyclohexoxy, cycloheptoxy, and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms, and typically from 1 to 12 carbons (C₁-C₁₂ alkyl), or, insome embodiments, from 1 to 8 carbon atoms (C₁-C₈ alkyl), or, in someembodiments, from 1 to 4 carbon atoms (C₁-C₄ alkyl). Alkyl groups may beoptionally substituted as defined herein. Examples of alkyl radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and thelike. The term “alkylene,” as used herein, alone or in combination,refers to a saturated aliphatic group derived from a straight orbranched chain saturated hydrocarbon attached at two or more positions,such as methylene (—CH₂—). Unless otherwise specified, the term “alkyl”may include “alkylene” groups.

Cycloalkyl groups are alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring do notgive rise to aromaticity. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like. Cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups can be mono-substituted orsubstituted one or more times with any of the groups listed above, forexample, but not limited to, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups.

Cycloalkylalkyloxy groups refer to alkyloxy groups as defined above inwhich a hydrogen or carbon bond of the alkyloxy group is replaced with abond to a cycloalkyl group as defined above. Examples of suchcycloalkylalkyloxy groups include, but are not limited to,cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy,cyclopropylbutoxy, cyclobutylmethoxy, cyclobutylethoxy,cyclobutylpropoxy, cyclobutylbutoxy, cyclopentylmethoxy,cyclopentylethoxy, cyclopentylpropoxy, cyclopentylbutoxy,cyclohexylmethoxy, cyclohexylethoxy, cyclohexylpropoxy,cyclohexylbutoxy, and the like.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —CC—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,Butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to aC(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently chosen from hydrogen, alkyl,acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,any of which may themselves be optionally substituted. Additionally, Rand R′ may combine to form heterocycloalkyl, either of which may beoptionally substituted.

The term “aryl,” as used herein, alone or in combination, refers to acyclic aromatic hydrocarbons that do not contain heteroatoms. Thus arylgroups include, but are not limited to, phenyl, azulenyl, heptalenyl,biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl,naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.In some embodiments, aryl groups contain 6-14 carbons in the ringportions of the groups. The phrase “aryl groups” includes groupscontaining fused rings, such as fused aromatic-aliphatic ring systems(e.g., indanyl, tetrahydronaphthyl, and the like), and also includessubstituted aryl groups that have other groups, including but notlimited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, oralkoxy groups, bonded to one of the ring atoms. Representativesubstituted aryl groups can be mono-substituted or substituted more thanonce, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or naphthyl groups, which can be substituted with groupsincluding but not limited to those listed above.

The compounds of the present invention may have a particular spatialarrangement of substituents on the aromatic rings, which is related tothe structure activity relationship demonstrated by the compound class.Often such substitution arrangement is denoted by a numbering system;however, numbering systems are often not consistent between differentring systems. In six-membered aromatic systems, the spatial arrangementsare specified by the common nomenclature “para” for 1,4-substitution,“meta” for 1,3-substitution and “ortho” for 1,2-substitution as shownbelow.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄═ derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NRC(O)O—) which may be attached to theparent molecular moiety from either the nitrogen or acid end, and whichmay be optionally substituted as defined herein. The term “O-carbamyl”as used herein, alone or in combination, refers to a —OC(O)NRR′ group;and the term “N-carbamyl” as used herein, alone or in combination,refers to a ROC(O)NR′— group. R and R′ are as defined herein, or asdefined by the specifically enumerated “R” groups designated.

The term “carbonyl,” as used herein, when alone includes formyl[-C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a C(O)OR groups where R isas defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom. Haloalkoxy includes perhaloalkoxy. The term “perhaloalkoxy”refers to an alkoxy group where all of the hydrogen atoms are replacedby halogen atoms. An example of perhaloalkoxy is perfluoromethoxy.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl, polyhaloalkyl, and perhaloalkyl radicals. Amonohaloalkyl radical, for one example, may have an iodo, bromo, chloroor fluoro atom within the radical. Dihalo and polyhaloalkyl radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals. Examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refersto a haloalkyl group attached at two or more positions. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like. Theterm “perhaloalkyl” as used herein, alone or in combination, refers toan alkyl group where all of the hydrogen atoms are replaced by halogenatoms. Examples include perfluoromethyl.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms chosen from O, N, and S, and whereinthe nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom chosenfrom O, S, and N. Additionally, a heteroaryl may contain one or twoC(O), S(O), or S(O)2 groups as ring members. In certain embodiments,said heteroaryl will comprise from 5 to 10 atoms. In certainembodiments, said heteroaryl will comprise from 5 to 7 atoms. In certainembodiments, said heteroaryl will comprise from 1 to 4 heteroatoms asring members. In further embodiments, said heteroaryl will comprise from1 to 2 heteroatoms as ring members. The term also embraces fusedpolycyclic groups wherein heterocyclic rings are fused with aryl rings,wherein heteroaryl rings are fused with other heteroaryl rings, whereinheteroaryl rings are fused with heterocycloalkyl rings, or whereinheteroaryl rings are fused with cycloalkyl rings. Examples of heteroarylgroups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, triazinyl, triazolyl,tetrazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl,benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl,tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclicheterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl,dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently chosenfrom N, O, and S. Additionally, a heterocycloalkyl may contain one ortwo C(O), S(O), or S(O)2 groups as ring members. In certain embodiments,said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ringmembers. In further embodiments, said heterocycloalkyl will comprisefrom 1 to 2 heteroatoms as ring members. In certain embodiments, saidheterocycloalkyl will comprise from 3 to 8 ring members in each ring. Infurther embodiments, said heterocycloalkyl will comprise from 3 to 7ring members in each ring. In yet further embodiments, saidheterocycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycloalkyls include furan-2-yl, furan-3-yl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, andmorpholinyl. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower alkyl,” as used herein, alone or in a combination, meansC₁-C₆ straight or branched chain alkyl. The term “lower alkenyl” meansC₂-C₆ straight or branched chain alkenyl. The term “lower alkynyl” meansC₂-C₆ straight or branched chain alkynyl.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomschosen from O, S, and N, or 2) bicyclic heteroaryl, wherein each of thefused rings comprises five or six ring members, comprising between themone to four heteroatoms chosen from O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomschosen from O, S, and N. Lower heterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently chosen from hydrogen, loweralkyl, and lower heteroalkyl, any of which may be optionallysubstituted. Additionally, the R and R′ of a lower amino group maycombine to form a five- or six-membered heterocycloalkyl, either ofwhich may be optionally substituted.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The term “oxy,” as used herein, alone or in combination, refer to —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms. Perhaloalkyl groups include, but are not limited to,—CF₃.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkoxy groupsinclude, but are not limited to, —OCF₃.

The term “haloalkyl” as used herein, alone or in combination, refers toan alkyl group where at least one of the hydrogen atoms are replaced byhalogen atoms. Haloalkyl groups include, but are not limited to,fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl,trifluoromethylethyl, and the like.

The term “haloalkoxy” refers to an alkoxy group where at least one ofthe hydrogen atoms are replaced by halogen atoms. Haloalkoxy groupsinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, and the like.

The term “arylene” refers to a divalent radical formed by the removal oftwo hydrogen atoms from one or more rings of an aryl group. One specificexample, the term “phenylene” refers to a divalent radical formed by theremoval of two hydrogen atoms from one or more rings of a phenyl group.Example of phenylene groups include

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “thio,” as used herein, alone or in combination, refer to a —S—group or an ether wherein the oxygen is replaced with sulfur. Theoxidized derivatives of the thio group, namely sulfinyl and sulfonyl,are included in the definition of thia and thio. The term “sulfanyl,” asused herein, alone or in combination, refers to —S—. The term“sulfinyl,” as used herein, alone or in combination, refers to —S(O)—.The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)2-.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety chosen fromhydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl, any of which may be optionally substituted. Such R andR′ groups should be understood to be optionally substituted as definedherein. Whether an R group has a number designation or not, every Rgroup, including R, R′ and Rn where n=(1, 2, 3, . . . n), everysubstituent, and every term should be understood to be independent ofevery other in terms of selection from a group. Should any variable,substituent, or term (e.g., aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.Those of skill in the art will further recognize that certain groups maybe attached to a parent molecule or may occupy a position in a chain ofelements from either end as written. Thus, by way of example only, anunsymmetrical group such as —C(O)N(R)— may be attached to the parentmoiety at either the carbon or the nitrogen.

When two “R” groups are said to be joined together or taken together toform a ring, it means that together with the carbon atom or a non-carbonatom (e.g., nitrogen atom), to which they are bonded, they may form aring system. In general, they are bonded to one another to form a 3- to7-membered ring, or a 5- to 7-membered ring. Non-limiting specificexamples are the cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl,piperazinyl, pyrolidinyl, pyrrolyl, pyridinyl.

Certain compounds disclosed herein contain one or more asymmetriccenters. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. Where a compound exists in various tautomeric forms, theinvention is not limited to any one of the specific tautomers, butrather includes all tautomeric forms. Certain compounds are describedherein using a general formula that includes variables. Unless otherwisespecified, each variable within such a formula is defined independentlyof other variables.

Compositions and Combination Treatments

Another embodiment of the invention provides compositions of thecompounds of the disclosure, alone or in combination with another MLKinhibitor or another type of therapeutic agent, or both.

In certain embodiments, the disclosure provides a pharmaceuticalcombination comprising a compound of the disclosure and a secondmedicament. In various embodiments, the second medicament (or secondtherapeutic agent) is medically indicated for the treatment of diseasesand conditions which can be affected by SGLT inhibition, such asantidiabetic agents, lipid-lowering/lipid-modulating agents, agents fortreating diabetic complications, anti-obesity agents, antihypertensiveagents, antihyperuricemic agents, and agents for treating chronic heartfailure, atherosclerosis or related disorders. Examples of secondmedicaments which can be used in combination with compounds disclosedherein include lithium, valproate and other agents used inneuroprotection, PAF receptor antagonists, antioxidants includingmitochondrially-targeted antioxidants, activators of SIRT₁ and othersirtuins, inhibitors of indoleamine 2,3 dehydrogenase (IDO), agentswhich enhance trans-blood brain bather (BBB) uptake of drugs, includingcompounds that inhibit drug pumps at the BBB, such as ritonavir; HAARTdrugs and other agents for use in HIV treatment; agents for thetreatment of cardiovascular, heart, and metabolic disorders, such asHMG-CoA reductase inhibitors including statins, insulin and insulinmimetics, and glycogen synthase kinase-3 beta (GSK3β) inhibitors; agentswhich “normalize” mitochondrial function; antinflammatory agentsincluding PAF receptor antagonists or PAF acetylhydrolase,cyclooxygenase inhibitors (including COX-2 selective and nonselective)such as aspirin, ibuprofen, naproxen, and celecoxib; and agents forblocking liver cell proliferation, such as JNK inhibitors.

In certain embodiments, the second medicament is used for the treatmentof HIV infection or AIDS. In certain of such embodimetns, the secondmedicament comprises atazanavir, ritonavir, zidovudine, lamivudine, orefavirenz.

In certain embodiments, MLK-3 antagonists may have a synergistic effecton HIV treatment.

In certain embodiments, the methods of treatment disclosed hereinadditionally comprise the administration of a second therapeutic agent,as part of a therapeutic regimen. The pharmaceutical combination (i.e.,the compounds of the present disclosure and a second medicament) can beadministered orally in the same dosage form, in a separate oral dosageform (e.g., sequentially or non-sequentially) or by injection togetheror separately (e.g., sequentially or non-sequentially).

The specific amount of the second therapeutic agent will depend on thespecific agent used, and the severity and stage of diseases, and theamount(s) of a MLK inhibitor and any optional additional active agentsconcurrently administered to the patient.

Method of Treatments

The disclosure is based, in part, on the belief that a MLK inhibitor canwork alone or in combination with another active agent to effectivelytreat a MLK-mediated disease.

In certain embodiments, a method is provided for treatment of aMLK-mediated disease where such method comprises administering aneffective amount to a subject a compound, pharmaceutical composition orpharmaceutical combination of the disclosure. In certain embodiments,such mammal is a human.

In certain embodiments, a method is provided for inhibiting theactivity, expression, or function of MLKs. In certain embodiments, thepresent disclosure provides selective inhibition. In certainembodiments, the disclosure provides a selective inhibitor providesselective inhibition of MLKs, especially MLK-3, over one or more otherkinases.

In certain embodiments, compounds according to the disclosure exhibit asurprising and unexpected selectivity in inhibiting a MLKs. In aspecific embodiment, compounds according to the disclosure exhibit asurprising and unexpected selectivity in inhibiting a MLK-3. Forexamples, when compared to the compounds described in Table 51, thecompounds according to the invention are surprisingly more selective fora MLK-3 over other kinases.

In certain embodiments, the present disclosure also provides a methodfor treatment of a MLK-mediated disease comprising administering to asubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound having the structure of Formula I

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein J has a structure of

where J can be optionally substituted with up to four R₁₀, each R₁₀ canbe independently selected from the group consisting of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR₆; X can be N R₁₂ or S;each X₁, X₂, X₃, and X₄ can be independently CH or N and wherein no morethan one of X₁, X₂, X₃, and X₄ can be N; Y can be —W—(CH₂)_(n)—R₁,

W can be null, phenylene, or —NR₆-phenylene, where the NR₆ can beattached to the imidazopyridazine core structure of Formula I; R₁ can be—NR₂R₃, or piperazinyl, where the nitrogen atom of the piperazinyl isoptionally substituted with alkyl or alkoxy; R₂ can be H or alkyl; R₃can be selected from the group consisting of C₂-C₁₀ alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, where any atom of R₃ canbe optionally substituted with one or more R₇; or R₂ and R₃ takentogether with the N atom to which they are attached form a 3- to7-membered heterocyclic ring optionally substituted with R₈; R₄ can be Hor alkyl; R₅ can be H, alkyl, or NHR₉; R₆ can be H or alkyl; each R₇ canbe independently alkyl, cycloalkyl, alkoxy, cycloalkoxy,cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR₁₁,or —O—(CH₂)_(m)—OH; R₈ can be alkoxy, hydroxyalkyl, or COOR₁₁; R₉ can beH, alkyl, or cycloalkyl; R₁₁ can be H, or alkyl; R₁₂ can be H, or alkyl;n can be 0 or 1; m can be 1, 2, or 3; and p can be 1, 2, or 3.

In certain embodiments, a method is provided for the preparation of amedicament useful for treating a MLK-mediated disease, where themedicament comprising a pharmaceutical composition disclosed herein.

Method of Making

Another embodiment of the invention provides methods for synthesis ofcertain compounds including compounds of the invention. In certain otherembodiments, the invention provides certain intermediate compoundsassociated with such methods of synthesis.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, the following examples are intended to illustrate but notlimit the scope of invention described in the claims.

General Synthetic Methods for Preparing Compounds

Molecular embodiments of the present invention can be synthesized usingstandard synthetic techniques known to those of skill in the art.Compounds of the present invention can be synthesized using the generalsynthetic procedures set forth in Schemes 1-64.

Example 1 Synthesis of Compounds 3-5, 195

Preparation of 6-chloroimidazo[1,2-b]pyridazine

Bromoacetaldehyde diethylacetal (13.7 g, 69.5 mmol, 1.8 equiv) was addedto hydrobromic acid (4.0 mL) and heated to reflux for 1.5 h. Thereaction mixture was cooled to rt then poured into a reaction flaskcontaining excess sodium bicarbonate in isopropanol. The solution wasstirred for 3 min and then filtered. To the mother liquor was added3-amino-6-chlorpyridazine (5.0 g, 38.6 mmol, 1.0 equiv) and heated toreflux for 2 h. The reaction mixture was quenched with water andextracted with ethyl acetate. Purification using column chromatographygave 5.1 g of the brown solid, 86%: ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s,1H), 7.88 (d, J=9.3 Hz, 1H), 7.74 (s, 1H), 7.01 (d, J=9.3 Hz, 1H).

Preparation of 6-chloro-3-iodoimidazo[1,2-b]pyridazine

6-chloroimidazo[1,2-b]pyridazine (2.0 g, 13.0 mmol, 1.0 equiv) inchloroform (20 mL) at room temperature was added N-iodosuccinimide (2.9g, 13.0 mmol, 1.0 equiv) then stirred vigorously overnight. The reactionmixture was diluted in water and extracted with ethyl acetate.Purification using column chromatography gave 3.3 g of the yellow solid,90%: 1H NMR δ 8.21 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 7.41 (d, J=7.6 Hz,1H).

Preparation of 6-chloro-3-(alkyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine

6-chloro-3-iodoimidazo[1,2-b]pyridazine (324 mg, 1.159 mmol, 1.0 equiv),in acetonitrile (10 mL), was addedmethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.51mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II) chloride (42 mg,0.0579 mmol, 0.05 equiv), then sodium carbonate (11.6 mL, 1.0 M aqueoussolution, 10 equiv). The reaction mixture was stirred overnight at roomtemperature. Purification by column chromatography gave of the product.

Preparation of3-(alkyl-1H-indol-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methoxy-1H-indol-2-yl)imidazo[1,2-b]pyridazine (59 mg,0.198 mmol, 1.0 equiv), xantphos (23 mg, 0.0395 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0198 mmol, 0.1 equiv), and potassiumcarbonate (546 mg, 3.95 mmol, 20 equiv) in dioxane (5.0 mL) was addedamine (0.395 mmol, 2.0 equiv) and heated to 100° C. for 2 h.Purification by column chromatography using 2% methanol indichloromethane elution gave the product.

TABLE 1-a Cd. Boronic Acid Amine Purified Compound Isolated 35-methoxy-2- 3,4- 3-(5-methoxy-1H-indol- (4,4,5,5- dimethoxyaniline2-yl)-N-(3,4- tetramethyl-1,3,2- dimethoxyphenyl)imidazo[1,2-dioxaborolan-2- b]pyridazin-6-amine yl)-1H-indole 4 6-methoxy- 3,4-3-(6-methoxy-1H-indol- 2-(4,4,5,5- dimethoxyaniline 2-yl)-N-(3,4-tetramethyl-1,3,2- dimethoxyphenyl)imidazo[1,2- dioxaborolan-2-b]pyridazin-6-amine yl)-1H-indole 5 7-methoxy-2- 3,4-3-(7-methoxy-1H-indol- (4,4,5,5- dimethoxyaniline 2-yl)-N-(3,4-tetramethyl-1,3,2- dimethoxyphenyl)imidazo[1,2- dioxaborolan-2-b]pyridazin-6-amine yl)-1H-indole 195 7-methyl-1H- 3, 4-N-(3,4-dimethoxyphenyl)-3-(7- indol-2- dimethoxyanilinemethyl-1H-indol-2- yl-2-boronic acid yl)imidazo[1,2- b]pyridazin-6-amine

Compounds 3-5, 195 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 1-b.

TABLE 1-b Cd. Structure IUPAC Name [M + H]⁺ 3

3-(5-methoxy-1H-indol-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6- amine 416.2 4

3-(6-methoxy-1H-indol-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6- amine 416.0 5

3-(7-methoxy-1H-indol-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6- amine 416.0 195

N-(3,4-dimethoxyphenyl)-3-(7-methyl-1H-indol-2-yl)imidazo[1,2-b]pyridazin-6-amine 400.2

Example 2 Synthesis of Compounds 85-88, 159, 196

Preparation of3-(alkyl-1H-indol-2-yl)-N-alkylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-(1H-indol-2-yl)imidazo[1,2-b]pyridazine (50mg, 0.167 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (32 mg, 0.167 mmol, 1.0 equiv) and amine (1.67 mmol,10.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gavethe product.

TABLE 2-a Cd. Boronic ester Amine Pure Isolated Compound 855-methoxy-2-(4,4,5,5- trans-4- trans-4-(3-(5-methoxy-1H-indol-tetramethyl-1,3,2- aminocyclohexanol 2-yl)imidazo[1,2-b]pyridazin-6-dioxaborolan-2-yl)- ylamino)cyclohexanol 1H-indole 866-methoxy-2-(4,4,5,5- trans-4- trans-4-(3-(6-methoxy-1H-indol-tetramethyl-1,3,2- aminocyclohexanol 2-yl)imidazo[1,2-b]pyridazin-6-dioxaborolan-2-yl)- ylamino)cyclohexanol 1H-indole 877-methoxy-2-(4,4,5,5- trans-4- trans-4-(3-(7-methoxy-1H-indol-tetramethyl-1,3,2- aminocyclohexanol 2-yl)imidazo[1,2-b]pyridazin-6-dioxaborolan-2-yl)- ylamino)cyclohexanol 1H-indole 88 1H-indol-2-yl-2-trans-4- trans-4-(3-(1H-indol-2- boronic acid aminocyclohexanolyl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 159 1H-indol-2-yl-2-1-propylamine 3-(1H-indol-2-yl)-N- boronic acidpropylimidazo[1,2-b]pyridazin- 6-amine 196 7-methyl-1H-indol-2- trans-4-trans-4-(3-(7-methyl-1H-indol- yl-2-boronic acid aminocyclohexanol2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 1985-methoxy-1H-indol- trans-4- trans-3-(5-methoxy-1H-indol-2-2-yl-2-boronic acid methoxycyclohexanamine yl)-N-(4-methoxycyclohexyl)imidazo[1,2- b]pyridazin-6-amine 1997-methoxy-1H-indol- trans-4- trans-3-(7-methoxy-1H-indol-2-yl)-N-(4-2-yl-2-boronic acid methoxycyclohexanaminemethoxycyclohexyl)imidazo[1,2- b]pyridazin-6-amine

Compounds 85-88, 159, 196, 198-199 were physically characterized byelectrospray ionization mass spectrometry. Structures and molecularmasses are given below in Table 2-b.

TABLE 2-b Cd. Structure IUPAC Name [M + H]⁺ 85

trans-4-(3-(5- methoxy-1H-indol- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 378.2 86

trans-4-(3-(6- methoxy-1H-indol- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 378.4 87

trans-4-(3-(7- methoxy-1H-indol- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 378.2 88

trans-4-(3-(1H- indol-2- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 348.5 159

3-(1H-indol-2-yl)- N- propylimidazo[1,2- b]pyridazin-6-amine 292.7 196

trans-4-(3-(7- methyl-1H-indol-2- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 362.2 198

trans-3-(5-methoxy- 1H-indol-2-yl)-N- (4- methoxycyclohexyl)imidazo[1,2- b]pyridazin-6-amine 392.5 199

trans-3-(7-methoxy- 1H-indol-2-yl)-N- (4- methoxycyclohexyl)imidazo[1,2- b]pyridazin-6-amine 392.3

Example 2C Synthesis of Compounds 193

Preparation of6-chloro-3-(5-methoxy-1-methyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine

To a solution of 5-methoxy-1-methyl-1H-indol-2-yl-2-boronic acid (243mg, 1.19 mmol, 1.2 equiv) in acetonitrile (9.88 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (276 mg, 0.988 mmol, 1.0 equiv),palladium catalyst (72 mg, 0.100 mmol, 0.1 equiv) and sodium carbonate(9.88 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave200 mg of the yellow solid, 65%.

Preparation of3-(5-methoxy-1-methyl-1H-indol-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5-methoxy-1-methyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine(49 mg, 0.157 mmol, 1.0 equiv), xantphos (18 mg, 0.0313 mmol, 0.2equiv), palladium acetate (4 mg, 0.0156 mmol, 0.1 equiv), and potassiumcarbonate (433 mg, 3.13 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (26 mg, 0.172 mmol, 1.1 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 40 mg, 0.152 mmol of the yellow solid, 59%.

Compound 193 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable X.

TABLE 2C Cd. Structure IUPAC Name [M + H]⁺ 193

3-(5-methoxy-1- methyl-1H-indol-2- yl)-N-(3,4- dimethoxyphenyl)imi-dazo[1,2-b]pyridazin- 6-amine 430.5

Example 2D Synthesis of Compound 194

Preparation oftrans-4-(3-(5-methoxy-1-methyl-1H-indol-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(5-methoxy-1-methyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine(50 mg, 0.160 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (30 mg, 0.160 mmol, 1.0 equiv) and amine(0.800 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reactionmixture was diluted with water and extracted with ethyl acetate.Purification by column chromatography using 5% methanol indichloromethane elution gave 35 mg of the yellow solid.

Compound 194 weal physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 2D.

TABLE 2D Cd. Structure IUPAC Name [M + H]⁺ 194

trans-4-(3-(5- methoxy-1-methyl- 1H-indol-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 392.3

Example 2E Synthesis of Compounds 197

Preparation of6-chloro-3-(5,6-dimethoxy-1-tosyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine

To a solution of5,6-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole(120 mg, 0.262 mmol, 1.0 equiv) in acetonitrile (3.41 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (95 mg, 0.341 mmol, 1.3 equiv),palladium catalyst (25 mg, 0.0341 mmol, 0.1 equiv) and sodium carbonate(3.41 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave80 mg of the yellow solid, 63%.

Preparation of3-(5,6-dimethoxy-1H-indol-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5,6-dimethoxy-1-tosyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine(68 mg, 0.141 mmol, 1.0 equiv), xantphos (16 mg, 0.0282 mmol, 0.2equiv), palladium acetate (3 mg, 0.0141 mmol, 0.1 equiv), and potassiumcarbonate (389 mg, 2.82 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (24 mg, 0.155 mmol, 1.1 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 20 mg of the yellow solid.

TABLE 2E Cd. Structure IUPAC Name [M + H]⁺ 197

3-(5,6-dimethoxy-1H-indol-2- yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 446.5

Example 3 Synthesis of Compounds 6-7

Preparation of 6-chloro-3-(naphthalen-1-yl)imidazo[1,2-b]pyridazine

To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (1.55 g, 10.1mmol) in 10.0 mL of toluene was added aryl bromide (2.11 mL, 15.1 mmol,1.5 equiv), potassium carbonate (2.79 g, 18.2 mmol, 2.0 equiv),triphenylphosphine (529 mg, 2.02 mmol, 0.2 equiv) and palladium acetate(227 mg, 1.01 mmol, 0.1 equiv). The solution was stirred to reflux for24 h. Purification by column chromatography using 50% ethyl acetate inhexanes elution gave 43% of the yellow solid.

Preparation of 3-(naphthalen-1-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-(naphthalen-1-yl)imidazo[1,2-b]pyridazine(50 mg, 0.179 mmol, 1.0 equiv), xantphos (21 mg, 0.0358 mmol, 0.2equiv), palladium acetate (4 mg, 0.0179 mmol, 0.1 equiv), and potassiumcarbonate (495 mg, 3.58 mmol, 20 equiv) in dioxane (5.0 mL) was addedamine (0.179 mmol, 1.0 equiv) and heated to 100° C. for 2 h.Purification by column chromatography using 2% methanol indichloromethane elution gave the product.

TABLE 3-a Cd. Amine Purified Compound Isolated 6 3,4-dimethoxyanilineN-(3,4-dimethoxyphenyl)-3- (naphthalen-1-yl)imidazo[1,2-b]pyridazin-6-amine 7 3-aminobenzoic acid 3-(3-(naphthalen-1-yl)imidazo[1,2-b]pyridazin-6- ylamino)benzoic acid

Compounds 6-7 were physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 3-b.

TABLE 3-b Cd. Structure IUPAC Name [M + H]⁺ 6

N-(3,4- dimethoxyphenyl)- 3-(naphthalen-1- yl)imidazo[1,2-b]pyridazin-6- amine 397.7 7

3-(3-(naphthalen-1- yl)imidazo[1,2- b]pyridazin-6- ylamino)benzoic acid381.8

Example 4 Synthesis of Compound 89

Preparation of4-(3-(naphthalen-1-yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol

To a solution of 6-chloro-3-(naphthalen-1-yl)imidazo[1,2-b]pyridazine(50 mg, 0.179 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (35 mg, 0.184 mmol, 1.0 equiv) and4-aminobutan-1-ol (200 mg, 2.24 mmol, 12.5 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 30 mg of a white solid, 50%.

Compound 89 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table4-b.

TABLE 4-b Cd. Structure IUPAC Name [M + H]⁺ 89

4-(3-(naphthalen-1- yl)imidazo[1,2- b]pyridazin-6- ylamino)butan-1-ol333.7

Example 5 Synthesis of Compounds 8, 17-21

Preparation of 6-chloro-2-methylimidazo[1,2-b]pyridazine

To a solution of 6-chloropyridazin-3-amine (2.35 g, 18.1 mmol, 1.0equiv) in ethanol (15 mL) was added 1-chloropropan-2-one (2.92 mL, 36.3mmol, 2.0 equiv) and triethylamine (2.53 mL, 18.1 mmol, 1.0 equiv). Thesolution was heated at 150° C. for 30 min then quenched with water.Purification by column chromatography using 30% ethyl acetate in hexaneselution gave 2.43 g of the brown solid, 80%.

Preparation of 3-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine

To a solution of 6-chloro-2-methylimidazo[1,2-b]pyridazine (2.00 g, 11.9mmol, 1.0 equiv) in chloroform (50 mL) was added N-bromosuccinimide(2.55 g, 14.3 mmol, 1.2 equiv). The reaction was stirred at roomtemperature for 15 h. Purification by column chromatography using 50%ethyl acetate in hexanes elution gave 2.64 g of the yellow solid, 90%.

Preparation of 6-chloro-2-methyl-3-arylimidazo[1,2-b]pyridazine

To a solution of 3-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (865mg, 5.16 mmol, 1.0 equiv) in acetonitrile (15 mL) was added boronic acid(5.16 mmol, 1.0 equiv), bis(triphenylphosphine)palladium(II) dichloride(0.516 mmol, 0.1 equiv), then sodium carbonate (1.0 M aqueous solution,10 equiv). The reaction mixture was irradiated in the microwave at 150°C. for 10 min. Purification by column chromatography gave of theproduct.

Preparation of 2-methyl-N,3-bisarylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-2-methyl-3-arylimidazo[1,2-b]pyridazine (100mg, 0.33 mmol, 1.0 equiv), xantphos (39 mg, 0.07 mmol, 0.2 equiv),palladium acetate (7 mg, 0.03 mmol, 0.1 equiv), and potassium carbonate(922 mg, 6.67 mmol, 20 equiv) in dioxane (5.0 mL) was added amine (0.367mmol, 1.1 equiv) and heated to 100° C. for 2 h. Purification by columnchromatography using 2% methanol in dichloromethane elution gave theproduct.

TABLE 5-a Cd. Boronic Acid Amine Purified Compound Isolated 83-methoxyphenylboronic 3,4-dimethoxyanilineN-(3,4-dimethoxyphenyl)-3-(3- acid methoxyphenyl)-2-methylimidazo[1,2-b]pyridazin- 6-amine 17 benzo[b]thiophen-2-yl-2-3,4-dimethoxyaniline 3-(benzo[b]thiophen-2-yl)-N- boronic acid(3,4-dimethoxyphenyl)-2- methylimidazo[1,2-b]pyridazin- 6-amine 18benzo[b]thiophen-2-yl-2- 3-(4-methylpiperazin-3-(benzo[b]thiophen-2-yl)-2- boronic acid 1-yl)benzenaminemethyl-N-(3-(4-methylpiperazin-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-amine 19 benzo[b]thiophen-2-yl-2- 4-(4-methylpiperazin-3-(benzo[b]thiophen-2-yl)-2- boronic acid 1-yl)benzenaminemethyl-N-(4-(4- methylpiperazin-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-amine 20 benzo[b]thiophen-2-yl-2- 3-((4-methylpiperazin-1-3-(benzo[b]thiophen-2-yl)-2- boronic acid yl)methyl)benzenaminemethyl-N-(3-((4- methylpiperazin-1- yl)methyl)phenyl)imidazo[1,2-b]pyridazin-6-amine 21 benzo[b]thiophen-2-yl-2- 4-((4-3-(benzo[b]thiophen-2-yl)-2- boronic acid methylpiperazin-1-methyl-N-(4-((4- yl)methyl)benzenamine methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazin-6-amine

Compounds 8, 17-21 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 5-b.

TABLE 5-b Cd. Structure IUPAC Name [M + H]⁺  8

N-(3,4-dimethoxyphenyl)-3- (3-methoxyphenyl)-2- methylimidazo[1,2-b]pyridazin-6-amine 391.7 17

3-(benzo[b]thiophen-2-yl)-N- (3,4-dimethoxyphenyl)-2- methylimidazo[1,2-b]pyridazin-6-amine 417.7 18

3-(benzo[b]thiophen-2-yl)-2- methyl-N-(3-(4- methylpiperazin-1-yl)phenyl)imidazo[1,2- b]pyridazin-6-amine 455.7 19

3-(benzo[b]thiophen-2-yl)-2- methyl-N-(4-(4- methylpiperazin-1-yl)phenyl)imidazo[1,2- b]pyridazin-6-amine 455.7 20

3-(benzo[b]thiophen-2-yl)-2- methyl-N-(3-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazin-6-amine 469.8 21

3-(benzo[b]thiophen-2-yl)-2- methyl-N-(4-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazin-6-amine 469.7

Example 6 Synthesis of Compounds 111-112, 114-115

Preparation of N-alkyl-2-methyl-3-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-2-methyl-3-arylimidazo[1,2-b]pyridazine (150mg, 0.500 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (95 mg, 0.500 mmol, 1.0 equiv) and amine (1.95 mmol,4.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gavethe product.

TABLE 6-a Cd. Boronic Acid Amine Purified Compound Isolated 111benzo[b]thiophen- trans-4- 4-(3-(benzo[b]thiophen- 2-yl-2-aminocyclohexanol 2-yl)-2- boronic acid methylimidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 112 benzo[b]thiophen- 2-methylpropan-1-3-benzo[b]thiophen- 2-yl-2- amine 2-yl)-N- boronic acid isobutyl-2-methylimidazo[1,2- b]pyridazin-6-amine 114 benzo[b]thiophen-N-methylpropyl-1- 3-(benzo[b]thiophen- 2-yl-2- amine 2-yl)-N,2- boronicacid dimethyl-N- propylimidazo[1,2- b]pyridazin-6-amine 115benzo[b]thiophen- pentan-1-amine 3-benzo[b]thiophen-2-yl)-2- 2-yl-2-methyl-N- boronic acid pentylimidazo[1,2- b]pyridazin-6-amine

Compounds 111-112, 114-115 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 6-b.

TABLE 6-b Cd. Structure IUPAC Name [M + H]⁺ 111

4-(3- (benzo[b]thiophen-2- yl)-2- methylimidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 379.7 112

3-(benzo[b]thiophen- 2-yl)-N-isobutyl-2- methylimidazo[1,2-b]pyridazin-6-amine 387.6 114

3-(benzo[b]thiophen- 2-yl)-N,2-dimethyl-N- propylimidazo[1,2-b]pyridazin-6-amine 337.7 115

3-(benzo[b]thiophen- 2-yl)-2-methyl-N- pentylimidazo[1,2-b]pyridazin-6-amine 353.8

Example 7 Synthesis of Compounds 9, 11

Preparation of3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of 3,4-dimethoxyaniline (178 mg, 1.16 mmol, 2.0 equiv) inTHF (5 mL) was added potassium tert-butoxide (131 mg, 1.16 mmol, 2.0equiv) and heated to 60° C. for 30 min. The reaction mixture was cooledto room temperature then 3-bromo-6-chloroimidazo[1,2-b]pyridazine (135mg, 0.582 mmol, 1.0 equiv) was added and stirred at room temperature for15 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 102 mg of the dark brown solid, 50%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (45 mg,0.129 mmol, 1.0 equiv) in acetonitrile (1.30 mL) was added boronic acid(0.193 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II) dichloride(0.013 mmol, 0.1 equiv), then sodium carbonate (1.0 M aqueous solution,10 equiv). The reaction mixture was irradiated in the microwave at 150°C. for 10 min. Purification by column chromatography gave of theproduct.

TABLE 7-a Cd. Boronic Acid Purified Compound Isolated  93-hydroxyphenylboronic 3-(6-(3,4- acid dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)phenol 11 3,4,5- 3-(3,4,5-trimethoxyphenyl)-N-(3,4-trimethoxyphenylboronic dimethoxyphenyl)imidazo[1,2- acidb]pyridazin-6-amine

Compounds 9, 11 were physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 7-b.

TABLE 7-b Cd. Structure IUPAC Name [M + H]⁺  9

3-(6-(3,4- dimethoxyphenylamino)imidazo[1,2- b]pyridazin-3-yl)phenol363.9 11

3-(3,4,5-trimethoxyphenyl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 437.4

Example 8 Synthesis of Compounds 12-16, 22-38, 41-45, 47-48

Preparation of3-(benzo[b]thiophen-2-yl)-6-chloroimidazo[1,2-b]pyridazine

To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (1.59 g, 10.3mmol, 1.1 equiv) in 28.0 mL of toluene was added2-bromobenzo[b]thiophene (2.00 g, 9.38 mmol, 1.0 equiv), potassiumcarbonate (2.59 g, 18.8 mmol, 2.0 equiv), triphenylphosphine (592 mg,1.88 mmol, 0.2 equiv) and palladium acetate (211 mg, 0.938 mmol, 0.1equiv). The solution was stirred to reflux for 24 h. Purification bycolumn chromatography using 50% ethyl acetate in hexanes elution gave1.50 g of the yellow solid, 56%.

Preparation of3-(benzo[b]thiophen-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-2-methyl-3-arylimidazo[1,2-b]pyridazine (100mg, 0.33 mmol, 1.0 equiv), xantphos (39 mg, 0.07 mmol, 0.2 equiv),palladium acetate (7 mg, 0.03 mmol, 0.1 equiv), and potassium carbonate(922 mg, 6.67 mmol, 20 equiv) in dioxane (5.0 mL) was added amine (0.367mmol, 1.1 equiv) and heated to 100° C. for 2 h. Purification by columnchromatography using 2% methanol in dichloromethane elution gave theproduct.

TABLE 8-a Cd. Amine Purified Compound Isolated 12 3,4-dimethoxyaniline3-(benzo[b]thiophen-2-yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 13 3-(4-methylpiperazin-1-3-(benzo[b]thiophen-2-yl)- yl)benzenamine N-(3-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2- b]pyridazin-6-amine 143,4,5-trimethoxybenzenamine 3-(benzo[b]thiophen-2-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 153-methoxybenzenamine 3-(benzo[b]thiophen-2-yl)-N-(3-methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 16 4-methoxybenzenamine3-(benzo[b]thiophen-2-yl)-N-(4- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 22 methyl 4-aminobenzoate methyl4-(3-(benzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)benzoate23 methyl 3-aminobenzoate methyl 3-(3-(benzo[b]thiophen-2-yl)imidazo[1,2- b]pyridazin-6-ylamino)benzoate 244-amino-2-methoxyphenol 4-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin- 6-ylamino)-2-methoxyphenol 25 methyl4-aminobenzoate 4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)benzoic acid 26 methyl 3-aminobenzoate3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin- 6-ylamino)benzoicacid 27 3-(4-amino-2- 3-(4-(3-(benzo[b]thiophen-methoxyphenoxy)propan-1-ol 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)-2-methoxyphenoxy)propan-1-ol 28 4-(cyclopropylmethoxy)-3-3-(benzo[b]thiophen-2-yl)-N-(4- methoxybenzenamine (cyclopropylmethoxy)-3-methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 294-(cyclopentylmethoxy)-3- 3-(benzo[b]thiophen-2-yl)-N-(4-methoxybenzenamine (cyclopentylmethoxy)-3- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 30 4-isopropoxy-3- 3-(benzo[b]thiophen-2-yl)-methoxybenzenamine N-(4-isopropoxy-3- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 31 5-amino-2-methoxyphenol 5-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin- 6-ylamino)-2-methoxyphenol 322,4-dimethoxybenzenamine 3-(benzo[b]thiophen-2-yl)-N-(2,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 33benzo[d][1,3]dioxol-5-amine 3-(benzo[b]thiophen-2-yl)-N-(benzo[d][1,3]dioxol-6- yl)imidazo[1,2-b]pyridazin-6-amine 342-methoxypyridin-4-amine 3-(benzo[b]thiophen-2-yl)-N-(2-methoxypyridin-4- yl)imidazo[1,2-b]pyridazin-6-amine 356-methoxypyridin-2-amine 3-(benzo[b]thiophen-2-yl)-N-(6-methoxypyridin-2- yl)imidazo[1,2-b]pyridazin-6-amine 362-methoxybenzenamine 3-(benzo[b]thiophen-2-yl)-N-(2-methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 372,3-dimethoxybenzenamine 3-(benzo[b]thiophen-2-yl)-N-(2,3-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 38 3,4-dihydro-2H-3-(benzo[b]thiophen-2-yl)- benzo[b][1,4]dioxepin- N-(3,4-dihydro-2H-7-amine benzo[b][1,4]dioxepin-8- yl)imidazo[1,2-b]pyridazin- 6-amine 412-methoxypyridin-4-amine 4-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin- 6-ylamino)pyridin-2-ol 42 3-(5-amino-2-3-(5-(3-(benzo[b]thiophen- methoxyphenoxy)propan-1-ol 2-yl)imidazo[1,2-b]pyridazin-6-ylamino)-2- methoxyphenoxy)propan-1-ol 43 methyl5-amino-2- 5-(3-(benzo[b]thiophen-2- methoxybenzoateyl)imidazo[1,2-b]pyridazin- 6-ylamino)-2-methoxybenzoic acid 44 methyl2-(3-hydroxypropoxy)- 5-(3-(benzo[b]thiophen-2- 5-aminobenzoateyl)imidazo[1,2-b]pyridazin- 6-ylamino)-2-(3- hydroxypropoxy)benzoic acid45 6-methoxypyridin-2-amine 6-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin- 6-ylamino)pyridin-2-ol 473,4-dichlorobenzenamine 3-(benzo[b]thiophen-2-yl)-N-(3,4-dichlorophenyl)imidazo[1,2- b]pyridazin-6-amine 48 3-3-(benzo[b]thiophen-2-yl)-N-(3- (trifluoromethoxy)benzenamine(trifluoromethoxy)phenyl)imidazo[1,2- b]pyridazin-6- amine

Compounds 12-16, 22-38, 41-45, 47-48 were physically characterized byelectrospray ionization mass spectrometry. Structures and molecularmasses are given below in Table 8-b.

TABLE 8-b Cd. Structure IUPAC Name [M + H]⁺ 12

3-(benzo[b]thiophen-2-yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 403.6 13

3-(benzo[b]thiophen-2-yl)-N-(3- (4-methylpiperazin-1-yl)phenyl)imidazo[1,2- b]pyridazin-6-amine 441.6 14

3-(benzo[b]thiophen-2-yl)-N- (3,4,5- trimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 433.7 15

3-(benzo[b]thiophen-2-yl)-N-(3- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 373.6 16

3-(benzo[b]thiophen-2-yl)-N-(4- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 373.6 22

methyl 4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)benzoate 401.6 23

methyl 3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)benzoate 401.7 24

4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-2-methoxyphenol 389.6 25

4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)benzoicacid 387.6 26

3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)benzoicacid 387.7 27

3-(4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)-2-methoxyphenoxy)propan-1-ol 447.6 28

3-(benzo[b]thiophen-2-yl)-N-(4- (cyclopropylmethoxy)-3-methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 443.7 29

3-(benzo[b]thiophen-2-yl)-N-(4- (cyclopentylmethoxy)-3-methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 457.7 30

3-(benzo[b]thiophen-2-yl)-N-(4- isopropoxy-3- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 431.8 31

5-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-2-methoxyphenol 389.8 32

3-(benzo[b]thiophen-2-yl)-N-(2,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 403.6 33

3-(benzo[b]thiophen-2-yl)-N- (benzo[d][1,3]dioxol-6-yl)imidazo[1,2-b]pyridazin-6- amine 387.6 34

3-(benzo[b]thiophen-2-yl)-N-(2- methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-amine 374.8 35

3-(benzo[b]thiophen-2-yl)-N-(6- methoxypyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine 376.8 36

3-(benzo[b]thiophen-2-yl)-N-(2- methoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 373.6 37

3-(benzo[b]thiophen-2-yl)-N-(2,3- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 403.7 38

3-(benzo[b]thiophen-2-yl)-N-(3,4- dihydro-2H- benzo[b][1,4]dioxepin-8-yl)imidazo[1,2-b]pyridazin-6- amine 415.8 41

4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)pyridin-2-ol 360.5 42

3-(5-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)-2-methoxyphenoxy)propan-1-ol 447.8 43

5-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-2-methoxybenzoic acid 417.9 44

5-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)-2-(3-hydroxypropoxy)benzoic acid 461.8 45

6-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)pyridin-2-ol 360.6 47

3-(benzo[b]thiophen-2-yl)-N-(3,4- dichlorophenyl)imidazo[1,2-b]pyridazin-6-amine 411.4, 415.4 48

3-(benzo[b]thiophen-2-yl)-N-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine 427.6

Example 9 Synthesis of Compounds 105, 107-110, 119, 122-127, 129-132,134-139

Preparation of3-(benzo[b]thiophen-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of3-(benzo[b]thiophen-2-yl)-6-chloroimidazo[1,2-b]pyridazine (100 mg,0.350 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (67 mg, 0.350 mmol, 1.0 equiv) and amine (1.75 mmol,5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gavethe product.

TABLE 9-a Cd. Amine Purified Compound Isolated 105trans-4-aminocyclohexanol trans-4-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 107N-methylpropan-1-amine 3-(benzo[b]thiophen-2-yl)-N-methyl-N-propylimidazo[1,2- b]pyridazin-6-amine 108 2-aminoethanol2-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)ethanol109 3-aminopropan-1-ol 3-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)propan-1-ol 110 4-aminobutan-1-ol4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol 119 2-(piperazin-1-yl)ethanol2-(4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanol 122 cis-3-aminocyclohexanolcis-3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 123 trans-3-aminocyclohexanoltrans-3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 124 (S)-2-methylpentan-3-amine3-(benzo[b]thiophen-2-yl)-N-((S)-2- methylpentan-3-yl)imidazo[1,2-b]pyridazin-6-amine 125 (R)-2-methylpentan-3-amine3-(benzo[b]thiophen-2-yl)-N-((R)-2- methylpentan-3-yl)imidazo[1,2-b]pyridazin-6-amine 126 ((R)-pyrrolidin-2-yl)methanol((R)-1-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)methanol 127 ((S)-pyrrolidin-2-yl)methanol((S)-1-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)methanol 129 (R)-2-amino-4-(R)-2-(3-(benzo[b]thiophen-2- methylpentan-1-olyl)imidazo[1,2-b]pyridazin-6- ylamino)-4-methylpentan-1-ol 130(S)-2-amino-4- (S)-2-(3-(benzo[b]thiophen-2- methylpentan-1-olyl)imidazo[1,2-b]pyridazin-6- ylamino)-4-methylpentan-1-ol 131 methylpiperidine- methyl 1-(3-(benzo[b]thiophen-2- 3-carboxylateyl)imidazo[1,2-b]pyridazin-6- yl)piperidine-3-carboxylate 132(piperidin-3-yl)methanol (1-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- yl)piperidin-3-yl)methanol 1344-tert-butylcyclohexanamine N-(4-tert-butylcyclohexyl)-3-(benzo[b]thiophen-2-yl)imidazo[1,2- b]pyridazin-6-amine 1355-aminopentan-1-ol 5-(3-(benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)pentan-1-ol 1363-(4-methylpiperazin-1- 3-(benzo[b]thiophen-2-yl)-N-(3-(4-yl)propan-1-amine methylpiperazin-1- yl)propyl)imidazo[1,2-b]pyridazin-6-amine 137 1-cyclohexylpiperidin-3-amine3-(benzo[b]thiophen-2-yl)-N-(1- cyclohexylpiperidin-3-yl)imidazo[1,2-b]pyridazin-6-amine 138 4-amino-2-methylbutan-1-ol4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-2-methylbutan-1-ol 139 trans-4- trans-4-(3-(benzo[b]thiophen-2-aminocyclohexyl)methanol yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexyl)methanol

Compounds 105, 107-110, 119, 122-127, 129-132, 134-139 were physicallycharacterized by electrospray ionization mass spectrometry. Structuresand molecular masses are given below in Table 9-b.

TABLE 9-B Cd. Structure IUPAC Name [M + H]⁺ 105

trans-4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 365.6 107

3-(benzo[b]thiophen-2-yl)-N- methyl-N-propylimidazo[1,2-b]pyridazin-6-amine 323.6 108

2-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)ethanol311.7 109

3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)propan-1-ol 325.6 110

4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol 339.7 119

2-(4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanol 380.8 122

cis-3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 365.8 123

trans-3-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 365.8 124

3-(benzo[b]thiophen-2-yl)-N-((S)- 2-methylpentan-3-yl)imidazo[1,2-b]pyridazin-6-amine 353.8 125

3-(benzo[b]thiophen-2-yl)-N- ((R)-2-methylpentan-3-yl)imidazo[1,2-b]pyridazin-6- amine 353.8 126

((R)-1-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)methanol 351.9 127

((S)-1-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)methanol 351.7 129

(R)-2-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-4-methylpentan-1-ol 367.7 130

(S)-2-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-4-methylpentan-1-ol 367.6 131

methyl 1-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylate 393.5 132

(1-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)methanol 365.8 134

N-(4-tert-butylcyclohexyl)-3- (benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 405.7 135

5-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)pentan-1-ol 353.6 136

3-(benzo[b]thiophen-2-yl)-N-(3- (4-methylpiperazin-1-yl)propyl)imidazo[1,2- b]pyridazin-6-amine 407.5 137

3-(benzo[b]thiophen-2-yl)-N-(1- cyclohexylpiperidin-3-yl)imidazo[1,2-b]pyridazin-6- amine 432.5 138

4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-2-methylbutan-1-ol 353.6 139

trans-4-(3-(benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexyl)methanol 379.7

Example 10 Synthesis of Compounds 39-40

Preparation of 3-(benzo[b]thiophen-2-yl)-6-arylimidazo[1,2-b]pyridazine

3-(benzo[b]thiophen-2-yl)-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.175mmol, 1.0 equiv), in acetonitrile (1.9 mL), was added the boronic ester(0.263 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II) chloride(12 mg, 0.018 mmol, 0.1 equiv), then sodium carbonate (1.0 M aqueoussolution, 10 equiv). The reaction mixture was irradiated at 150° C. for10 min. Purification by column chromatography gave of the product.

TABLE 10-a Cd. Boronic Ester Purified Compound Isolated 391-(4-(4,4,5,5-tetramethyl- 3-(benzo[b]thiophen-2-yl)-6-(4((4-1,3,2-dioxaborolan- methylpiperazin-1- 2-yl)benzyl)-4-methylpiperazineyl)methyl)phenyl)imidazo[1,2- b]pyridazine 40 1-(3-(4,4,5,5-tetramethyl-3-(benzo[b]thiophen-2-yl)-6-(3((4- 1,3,2-dioxaborolan-methylpiperazin-1- 2-yl)benzyl)-4-methylpiperazineyl)methyl)phenyl)imidazo[1,2- b]pyridazine

Compounds 39-40 were physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 10-b.

TABLE 10-B Cd. Structure IUPAC Name [M + H]⁺ 39

3-(benzo[b]thiophen-2-yl)-6- (4-((4-methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazine 440.7 40

3-(benzo[b]thiophen-2-yl)-6- (3-((4-methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazine 440.7

Example 11 Synthesis of Compound 46

Preparation of 6-chloro-N-cyclopropylimidazo[1,2-b]pyridazin-8-amine

To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.00 g, 3.21mmol, 1.0 equiv) and p-TSA (611 mg, 3.21 mmol, 1.0 equiv) in DMSO (10.0mL) was added cyclopropylamine (1.13 mL, 16.1 mmol, 5.0 equiv) andheated to 100° C. for 24 h. Purification by column chromatography using50% ethyl acetate in hexanes elution gave 536 mg of the white solid,80%.

Preparation of tert-butyl6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-8-ylcyclopropylcarbamate

To a solution of 6-chloro-N-cyclopropylimidazo[1,2-b]pyridazin-8-amine(99 mg, 0.473 mmol, 1.0 equiv) in acetonitrile (2.00 mL) was addeddi-tert-butyl dicarbonate (103 mg, 0.473 mmol, 1.0 equiv) and stirred atroom temperature for 15 h. The reaction mixture was diluted with waterand extracted with ethyl acetate and concentrated in vacuo. The crudematerial was diluted in dioxane (5.00 mL) and 3,4-dimethoxyaniline (109mg, 0.709 mmol, 1.3 equiv), xantphos (55 mg, 0.0946 mmol, 0.2 equiv),palladium acetate (11 mg, 0.0473 mmol, 0.1 equiv) and potassiumcarbonate (1.31 g, 9.46 mmol, 20 equiv) was added. The reaction mixturewas heated in the microwave at 150° C. for 10 minutes. Purification bycolumn chromatography using 2% methanol in hexanes elution gave 173 mgof the brown solid, 86%.

Preparation of bis-Boc-Protected Pyridazine

To a solution of tert-butyl6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-8-ylcyclopropylcarbamate(173 mg, 0.407 mmol, 1.0 equiv) in acetonitrile (5.00 mL) was addeddi-tert-butyl dicarbonate (177 mg, 0.813 mmol, 2.0 equiv) and catalytic4-dimethylaminopyridine. After 15 h, the reaction was diluted with waterand extracted with ethyl acetate. The crude material was diluted inchloroform (10.0 mL) and N-bromosuccinimide (72 mg, 0.407 mmol, 1.0equiv) and heated to 70° C. for 20 minutes. Purification by columnchromatography using 50% ethyl acetate in hexanes elution gave 214 mg ofthe yellow solid, 87%

Preparation of3-bromo-N₈-cyclopropyl-N₆-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine

To the bis-Boc-protected pyridazine (99 mg, 0.163 mmol, 1.0 equiv) indichloromethane (5.00 mL) was added excess trifluoroacetic acid (1.00mL) and stirred for 3 h. The reaction was diluted with water andextracted with ethyl acetate. Purification by column chromatographyusing 2% methanol in hexanes elution gave 66 mg of the brown solid,100%.

Preparation of3-(benzo[b]thiophen-2-yl)-N₈-cyclopropyl-N₆-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine

To a solution of3-bromo-N₈-cyclopropyl-N₆-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine(66 mg, 0.163 mmol, 1.0 equiv) in acetonitrile (1.63 mL), was addedbenzo[b]thiophen-2-yl-2-boronic acid (58 mg, 0.327 mmol, 2.0 equiv),bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.0163 mmol, 0.1equiv), then sodium carbonate (1.63 mL, 1.0 M aqueous solution, 10equiv). The reaction mixture was irradiated at 150° C. for 10 min.Purification by column chromatography gave 26 mg of the brown solid,34%.

Compound 46 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table11-b.

TABLE 11-B Cd. Structure IUPAC Name [M + H]⁺ 46

3-(benzo[b]thiophen-2-yl)-N₈- cyclopropyl-N₆-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazine-6,8-diamine 458.8

Example 12 Synthesis of Compounds 49-50, 59

Preparation of 6-chloro-3-(1H-indol-5-yl)imidazo[1,2-b]pyridazine

6-chloro-3-iodoimidazo[1,2-b]pyridazine (1.00 g, 4.30 mmol, 1.0 equiv),in acetonitrile (20 mL), was added 1H-indol-5-yl-5-boronic acid (1.04 g,6.45 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II) chloride(157 mg, 0.215 mmol, 0.05 equiv), then sodium carbonate (4.83 mL, 1.0 Maqueous solution, 2.0 equiv). The reaction mixture heated in themicrowave at 150° C. for 20 min. Purification by column chromatographyusing 2% methanol in dichloromethane elutions gave 1.04 g of the whitesolid, 60%.

Preparation of 3-(1H-indol-5-yl)-6-arylimidazo[1,2-b]pyridazine

6-chloro-3-(1H-indol-5-yl)imidazo[1,2-b]pyridazine (60 mg, 0.223 mmol,1.0 equiv), in acetonitrile (1.00 mL), was added boronic acid (0.241mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II) chloride (2 mg,0.002, 0.01 equiv), then sodium carbonate (1.00 mL, 1.0 M aqueoussolution). The reaction mixture heated in the microwave at 150° C. for10 min. Purification by column chromatography using 5% methanol inhexanes elution gave the product.

TABLE 12-a Cd. Boronic Ester Purified Compound Isolated 491-(4-(4,4,5,5-tetramethyl-1,3, 3-(1H-indol-5-yl)-6-(4-((4-2-dioxaborolan-2-yl)benzyl)- methylpiperazin-1- 4-methylpiperazineyl)methyl)phenyl)imidazo[1,2- b]pyridazine 50 1H-indol-5-yl-5-boronicacid 3,6-di(1H-indol-5-yl)imidazo[1, 2-b]pyridazine 593,4,5-trimethoxyphenylboronic 3-(1H-indol-5-yl)-6-(3,4,5- acidtrimethoxyphenyl)imidazo[1,2- b]pyridazine

Compounds 49-50, 59 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 12-b.

TABLE 12-B Cd. Structure IUPAC Name [M + H]⁺ 49

3-(1H-indol-5-yl)-6-(4-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazine 423.6 50

3,6-di(1H-indol-5- yl)imidazo[1,2-b]pyridazine 350.6 59

3-(1H-indol-5-yl)-6-(3,4,5- trimethoxyphenyl)imidazo[1,2- b]pyridazine401.6

Example 13 Synthesis of Compounds 52-58, 60-61

Preparation of 3-(1H-indol-5-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-(1H-indol-5-yl)imidazo[1,2-b]pyridazine (50mg, 0.186 mmol, 1.0 equiv), xantphos (22 mg, 0.0372 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0186 mmol, 0.1 equiv), and potassiumcarbonate (514 mg, 3.72 mmol, 20 equiv) in dioxane (5.0 mL) was addedamine (0.279 mmol, 1.5 equiv) and heated to 100° C. for 2 h.Purification by column chromatography using 2% methanol indichloromethane elution gave the product.

TABLE 13-a Cd. Amine Purified Compound Isolated 52 4-methoxybenzenamine3-(1H-indol-5-yl)-N-(4- methoxyphenyl)imidazo[1,2-b]pyridazin- 6-amine53 3,4-dimethoxyaniline 3-(1H-indol-5-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin- 6-amine 54 3-methoxybenzenamine3-(1H-indol-5-yl)-N-(3- methoxyphenyl)imidazo[1,2-b]pyridazin- 6-amine55 4-(4-methylpiperazin-1- 3-(1H-indol-5-yl)-N-(4-(4-methylpiperazin-yl)benzenamine 1-yl)phenyl)imidazo[1,2-b]pyridazin-6- amine 563-(4-methylpiperazin-1- 3-(1H-indol-5-yl)-N-(3-(4-methylpiperazin-yl)benzenamine 1-yl)phenyl)imidazo[1,2-b]pyridazin-6- amine 574-((4-methylpiperazin-1- 3-(1H-indol-5-yl)-N-(4-((4-methylpiperazin-yl)methyl)benzenamine 1-yl)methyl)phenyl)imidazo[1,2-b]pyridazin-6-amine 58 3-((4-methylpiperazin-1-3-(1H-indol-5-yl)-N-(3-((4-methylpiperazin- yl)methyl)benzenamine1-yl)methyl)phenyl)imidazo[1,2- b]pyridazin-6-amine 60 methyl4-aminobenzoate methyl 4-(3-(1H-indol-5-yl)imidazo[1,2-b]pyridazin-6-ylamino)benzoate 61 methyl 3-aminobenzoate methyl3-(3-(1H-indol-5-yl)imidazo[1,2- b]pyridazin-6-ylamino)benzoate

Compounds 52-58, 60-61 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 13-b.

TABLE 13-B Cd. Structure IUPAC Name [M + H]⁺ 52

3-(1H-indol-5-yl)-N-(4- methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine356.7 53

3-(1H-indol-5-yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 386.6 54

3-(1H-indol-5-yl)-N-(3- methoxyphenyl)imidazo[1,2- b]pyridazin-6-amine356.7 55

3-(1H-indol-5-yl)-N-(4-(4- methylpiperazin-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-amine 424.8 56

3-(1H-indol-5-yl)-N-(3-(4- methylpiperazin-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-amine 424.8 57

3-(1H-indol-5-yl)-N-(4-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazin-6-amine 438.8 58

3-(1H-indol-5-yl)-N-(3-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazin-6-amine 438.8 60

methyl 4-(3-(1H-indol-5- yl)imidazo[1,2-b]pyridazin-6- ylamino)benzoate398.6 61

methyl 3-(3-(1H-indol-5- yl)imidazo[1,2-b]pyridazin-6- ylamino)benzoate384.7

Example 14 Synthesis of Compounds 140-143, 148-150, 158

Preparation of 3-(1H-indol-5-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-(1H-indol-5-yl)imidazo[1,2-b]pyridazine (150mg, 0.500 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (95 mg, 0.500 mmol, 1.0 equiv) and amine (1.95 mmol,4.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gavethe product.

TABLE 14-a Cd. Amine Purified Isolated Compound 140 propan-1-amine3-(1H-indol-5-yl)-N-propylimidazo[1, 2-b]pyridazin-6-amine 141trans-4-aminocyclohexanol trans-4-(3-(1H-indol-5-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 142 2-methylpropan-1-amine3-(1H-indol-5-yl)-N-isobutylimidazo[1, 2-b]pyridazin-6-amine 1432-aminoethanol 2-(3-(1H-indol-5-yl)imidazo[1,2-b]pyridazin-6-ylamino)ethanol 148 cyclopropanamineN-cyclopropyl-3-(1H-indol-5- yl)imidazo[1,2-b]pyridazin-6-amine 149(R)-butan-2-amine N-sec-butyl-3-(1H-indol-5-yl)imidazo[1,2-b]pyridazin-6-amine 150 cyclopropylmethanamineN-(cyclopropylmethyl)-3-(1H-indol-5- yl)imidazo[1,2-b]pyridazin-6-amine158 N-methylpropan-1-amine 3-(1H-indol-5-yl)-N-methyl-N-propylimidazo[1,2-b]pyridazin-6-amine

Compounds 140-143, 148-150, 158 were physically characterized byelectrospray ionization mass spectrometry. Structures and molecularmasses are given below in Table 14-b.

TABLE 14-B Cd. Structure IUPAC Name [M + H]⁺ 140

3-(1H-indol-5-yl)-N- propylimidazo[1,2- b]pyridazin-6-amine 292.5 141

trans-4-(3-(1H-indol- 5-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 348.7 142

3-(1H-indol-5-yl)-N- isobutylimidazo[1,2- b]pyridazin-6-amine 306.7 143

2-(3-(1H-indol-5- yl)imidazo[1,2- b]pyridazin-6- ylamino)ethanol 294.6148

N-cyclopropyl-3-(1H- indol-5- yl)imidazo[1,2- b]pyridazin-6-amine 290.6

149

N-sec-butyl-3-(1H- indol-5- yl)imidazo[1,2- b]pyridazin-6-amine 306.7150

N- (cyclopropylmethyl)- 3-(1H-indol-5- yl)imidazo[1,2-b]pyridazin-6-amine 304.6 158

3-(1H-indol-5-yl)-N- methyl-N- propylimidazo[1,2- b]pyridazin-6-amine306.7

Example 15 Synthesis of Compounds 62-65

Preparation of 6-chloro-3-arylimidazo[1,2-b]pyridazine

To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (404 mg, 2.63mmol, 1.0 equiv) in 10.0 mL of toluene was added aryl bromide (1.00 g,3.95 mmol, 1.5 equiv), potassium carbonate (728 mg, 5.27 mmol, 2.0equiv), triphenylphosphine (138 mg, 0.527 mmol, 0.2 equiv) and palladiumacetate (59 mg, 0.263 mmol, 0.1 equiv). The solution was stirred toreflux for 24 h. Purification by column chromatography using 50% ethylacetate in hexanes elution gave the product.

Preparation of N,3-bisarylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-arylimidazo[1,2-b]pyridazine (50 mg, 0.179mmol, 1.0 equiv), xantphos (21 mg, 0.0358 mmol, 0.2 equiv), palladiumacetate (4 mg, 0.0179 mmol, 0.1 equiv), and potassium carbonate (495 mg,3.58 mmol, 20 equiv) in dioxane (5.0 mL) was added amine (0.179 mmol,1.0 equiv) and heated to 100° C. for 2 h. Purification by columnchromatography using 2% methanol in dichloromethane elution gave theproduct.

TABLE 15-a Cd. Arylbromide Amine Purified Isolated Compound 62 2- 3,4-N-(3,4-dimethoxyphenyl)-3- bromonaphthalene dimethoxyaniline(naphthalen-3-yl)imidazo[1, 2-b]pyridazin-6-amine 63 2- methyl 3-3-(3-(naphthalen-3- bromonaphthalene aminobenzoateyl)imidazo[1,2-b]pyridazin- 6-ylamino)benzoic acid 64 2-bromo-6- 3,4-3-(2-fluoronaphthalen-6-yl)- fluoronaphthalene dimethoxyaniline N-(3,4-dimethoxyphenyl)imidazo[1, 2-b]pyridazin-6-amine 65 2-bromo-6- 3,4-3-(2-methoxynaphthalen-6- methoxynaphthalene dimethoxyanilineyl)-N-(3,4- dimethoxyphenyl)imidazo[1, 2-b]pyridazin-6-amine

Compounds 62-65 were physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 15-b.

TABLE 15-B Cd. Structure IUPAC Name [M + H]⁺ 62

N-(3,4-dimethoxyphenyl)-3- (naphthalen-3-yl)imidazo[1,2-b]pyridazin-6-amine 397.6 63

3-(3-(naphthalen-3- yl)imidazo[1,2-b]pyridazin-6- ylamino)benzoic acid381.7 64

3-(2-fluoronaphthalen-6-yl)- N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 415.8 65

3-(2-methoxynaphthalen-6- yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 427.7

Example 16 Synthesis of Compounds 160-163

Preparation of N-alkyl-3-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-2-methyl-3-arylimidazo[1,2-b]pyridazine (150mg, 0.500 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (95 mg, 0.500 mmol, 1.0 equiv) and amine (1.95 mmol,4.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gavethe product.

TABLE 16-a Purified Isolated Cd. Arylbromide Amine Compound 1602-bromonaphthalene 4-aminobutan-1-ol 4-(3-(naphthalen-3- yl)imidazo[1,2-b[pyridazin-6- ylamino)butan-1-ol 161 2-bromonaphthalene trans-4-trans-4-(3-(naphthalen- aminocyclohexanol 3-yl)imidazo[1,2-b[pyridazin-6- ylamino)cyclohexanol 162 2-bromo- trans-4- trans-4-(3-(2-6-fluoronaphthalene aminocyclohexanol fluoronaphthalen-6-yl)imidazo[1,2- b[pyridazin-6- ylamino)cyclohexanol 163 2-bromo-trans-4- trans-4-(3-(2- 6-methoxynaphthalene aminocyclohexanolmethoxynaphthalen-6- yl)imidazo[1,2- b[pyridazin-6- ylamino)cyclohexanol

Compounds 160-163 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 16-b.

TABLE 16-B Cd. Structure IUPAC Name [M + H]⁺ 160

4-(3-(naphthalen-3- yl)imidazo[1,2- b]pyridazin-6- ylamino)butan-1-ol333.7 161

trans-4-(3- (naphthalen-3- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 359.8 162

trans-4-(3-(2- fluoronaphthalen-6- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 377.8 163

trans-4-(3-(2- methoxynaphthalen-6- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 389.9

Example 17 Synthesis of Compound 68, 181-185

Preparation of6-chloro-3-(7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 7-methoxybenzo[b]thiophen-2-yl-2-boronic acid (49 mg,0.237 mmol, 1.1 equiv) in acetonitrile (2.15 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (50 mg, 0.215 mmol, 1.0 equiv),palladium catalyst (8 mg, 0.0108 mmol, 0.05 equiv) and sodium carbonate(2.15 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave48 mg of the yellow solid, 70%.

Preparation of3-(7-methoxybenzo[b]thiophen-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (82mg, 0.260 mmol, 1.0 equiv), xantphos (30 mg, 0.0519 mmol, 0.2 equiv),palladium acetate (6 mg, 0.0260 mmol, 0.1 equiv), and potassiumcarbonate (718 mg, 5.19 mmol, 20 equiv) in dioxane (5.0 mL) was addedsubstituted aniline (48 mg, 0.312 mmol, 1.1 equiv) and heated to 110° C.for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave the product.

TABLE 17A Cd. Amine Purified Isolated Compound  68 3,4-dimethoxyaniline3-(7-methoxybenzo[b]thiophen- 2-yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 181 4-ethoxy-3- N-(4-ethoxy-3- methoxybenzenaminemethoxyphenyl)-3-(7- methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 182 3-methoxy-4- N-(3-methoxy-4-propoxybenzenamine propoxyphenyl)-3-(7- methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 183 4-(difluoromethoxy)-3-N-(4-(difluoromethoxy)-3- methoxybenzenamine methoxyphenyl)-3-(7-methoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- amine 1843-methoxy-4- N-(3-methoxy-4- (trifluoromethoxy)benzenamine(trifluoromethoxy)phenyl)-3-(7- methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 185 4-methoxy-3- N-(4-methoxy-3-(trifluoromethoxy)benzenamine (trifluoromethoxy)phenyl)-3-(7-methoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- amine

Compound 68, 181-185 was physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table x-x.

TABLE 17-B Cd. Structure IUPAC Name [M + H]⁺  68

3-(7- methoxybenzo[b]thiophen-2- yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 433.2 181

N-(4-ethoxy-3- methoxyphenyl)-3-(7- methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 447.1 182

N-(3-methoxy-4- propoxyphenyl)-3-(7- methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 461.3 183

N-(4-(difluoromethoxy)-3- methoxyphenyl)-3-(7-methoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6- amine 469.1 184

N-(3-methoxy-4- (trifluoromethoxy)phenyl)-3- (7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin- 6-amine 487.1 185

N-(4-methoxy-3- (trifluoromethoxy)phenyl)-3- (7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin- 6-amine 487.4

Example 18 Synthesis of Compounds 170 and 200

Preparation oftrans-4-(3-(7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidaczo[1,2-b]pyridazine (50mg, 0.111 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (30 mg, 0.111 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.803 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 35 mg of the yellow solid, 80%.

Compounds 170 and 200 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 18-b.

TABLE 18-B Cd. Amine Structure IUPAC Name [M + H]⁺ 170 trans-4-aminocyclohexanol

trans-4-(3-(7- methoxybenzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 395.5 200 trans-4- methoxycyclohexanamine

trans-3-(7- methoxybenzo[b]thiophen- 2-yl)-N-(4- methoxycyclohexyl)imidazo[1,2-b]pyridazin-6- amine 409.1

Example 19A Synthesis of Compounds 78-81 and 186-188

Preparation of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-ol

To a solution of6-chloro-3-(7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (103mg, 0.326 mmol, 1.0 equiv) in dichloromethane at −78° C. was added borontribromide (2.27 mL, 1.0 M solution in dichloromethane, 7.0 equiv). Thereaction mixture was stirred at the reduced temperature for 10 min thenwarmed to room temperature and stirred for 15 h. Methanol (2 mL) wasadded to quench the reaction and extracted with dichloromethane.Purification by column chromatography using 5% methanol indichloromethane elution gave 70 mg of the yellow solid, 70%.

Preparation of6-chloro-3-(7-alkoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-ol (33 mg,0.109 mmol, 1.0 equiv) in acetone (2 mL) was added potassium carbonate(30 mg, 0.219 mmol, 2.0 equiv) and alkyl halide (0.219 mmol, 2.0 equiv)and heated to reflux for 15 h. Purification by column chromatographyusing 2% methanol in dichloromethane elution gave the product.

Preparation of3-(7-alkoxybenzo[b]thiophen-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-alkoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (38mg, 0.109 mmol, 1.0 equiv), xantphos (0.022 mmol, 0.2 equiv), palladiumacetate (0.011 mmol, 0.1 equiv), and potassium carbonate (2.19 mmol, 20equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (0.164 mmol,1.5 equiv) and heated to 100° C. for 2 h. Purification by columnchromatography using 2% methanol in dichloromethane elution gave theproduct.

TABLE 19-a Cd. Alkyl halide Purified Isolated Compound  78 acetylchloride 2-(6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-yl acetate  792-(6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-ol  80 2-iodopropane3-(7-isopropoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine  81 1-iodopropaneN-(3,4-dimethoxyphenyl)-3-(7- propoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-amine 186 Ethyliodide3-(7-ethoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6- amine 187 sodium 2-chloro-3-(7-(difluoromethoxy)benzo[b]thiophen-2- 2,2-difluoroacetateyl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 188trifluoroiodomethane N-(3,4-dimethoxyphenyl)-3-(7-(trifluoromethoxy)benzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-amine

Compounds 78-81, 186-188 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 19-A.

TABLE 19-B Cd. Structure IUPAC Name [M + H]⁺  78

2-(6-(3,4- dimethoxyphenylamino)imidazo [1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-yl acetate 461.3  79

2-(6-(3,4- dimethoxyphenylamino)imidazo [1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-ol 419.4  80

3(7- isopropoxybenzo[b]thiophen-2- yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 461.4  81

N-(3,4-dimethoxyphenyl)-3-(7- propoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 461.5 186

3-(7-ethoxybenzo[b]thiophen-2- yl)-N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 447.2 187

3-(7- (difluoromethoxy)benzo[b] thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo [1,2-b]pyridazin-6-amine 469.3 188

N-(3,4-dimethoxyphenyl)-3-(7- (trifluoromethoxy)benzo[b]thiophen-2-yl)imidazo [1,2-b]pyridazin-6-amine 487.3

Example 19B Synthesis of Compounds 189-190

Preparation ofN-aryl-3-(7-(trifluoromethoxy)benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-(trifluoromethoxy)benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(55 mg, 0.164 mmol, 1.0 equiv), xantphos (0.033 mmol, 0.2 equiv),palladium acetate (0.016 mmol, 0.1 equiv), and potassium carbonate (3.28mmol, 20 equiv) in dioxane (5.0 mL) was added substituted aniline (0.164mmol, 1.0 equiv) and heated to 100° C. for 2 h. Purification by columnchromatography using 2% methanol in dichloromethane elution gave theproduct.

TABLE 19C Cd. Amine Purified Isolated Compound 1894-(difluoromethoxy)-3- N-(4-(difluoromethoxy)-3-methoxyphenyl)-3-methoxybenzenamine (7-(trifluoromethoxy)benzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-amine 190 N-(3-methoxy-4-N-(3-methoxy-4-(trifluoromethoxy)phenyl)-3-(trifluoromethoxy)phenyl)-3-(7- (7-(trifluoromethoxy)benzo[b]thiophen-2-(trifluoromethoxy)benzo[b]thiophen- yl)imidazo[1,2-b]pyridazin-6-amine2-yl)imidazo[1,2-b]pyridazin-6-amine

Compounds 189-190 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 19D.

TABLE 19D Cd. Structure IUPAC Name [M + H]⁺ 189

N-(4-(difluoromethoxy)-3- methoxyphenyl)-3-(7-(trifluoromethoxy)benzo[b] thiophen-2-yl)imidazo[1,2-b]pyridazin-6-amine 523.1 190

N-(3-methoxy-4- (trifluoromethoxy)phenyl)-3-(7-(trifluoromethoxy)benzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6-amine541.4

Example 20 Synthesis of Compound 77

Preparation of2-(6-trans-4-hydroxycyclohexylamino)imidazo[1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-ol

To a solution of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzo[b]thiophen-7-ol (50 mg,0.166 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (32 mg, 0.167 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (95 mg, 0.830 mmol, 5.0 equiv) and heated to100° C. for 24 h. The reaction mixture was diluted with water andextracted with ethyl acetate. Purification by column chromatographyusing 5% methanol in dichloromethane elution gave 40 mg of the yellowsolid, 79%.

Compound 77 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table20-b.

TABLE 20-B Cd. Structure IUPAC Name [M + H]⁺ 77

2-(6-trans-4- hydroxycyclohexylamino) imidazo[1,2-b]pyridazin-3-yl)benzo [b]thiophen-7-ol 381.3

Example 21A Synthesis of Compound 178

Preparation oftrans-4-(3-(7-isopropoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(7-isopropoxybenzo[b]thiophen-2-yl)imidaczo[1,2-b]pyridazine(56 mg, 0.167 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (32 mg, 0.167 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.828 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 25 mg of the yellow solid, 36%.

Compound 178 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 21-b.

TABLE 21-B Cd. Structure IUPAC Name [M + H]⁺ 178

trans-4-(3-(7- isopropoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 423.2

Example 21A Synthesis of Compound 202

Preparation of6-chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 6-methylbenzo[b]thiophen-2-yl-2-boronic acid (100 mg,0.521 mmol, 1.1 equiv) in acetonitrile (4.73 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (132 mg, 0.473 mmol, 1.0 equiv),palladium catalyst (35 mg, 0.0473 mmol, 0.1 equiv) and sodium carbonate(4.73 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave110 mg of the yellow solid, 78%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50mg, 0.167 mmol, 1.0 equiv), xantphos (19 mg, 0.0334 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0167 mmol, 0.1 equiv), and potassiumcarbonate (461 mg, 3.34 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (21 mg, 0.184 mmol, 1.1 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 40 mg, 0.195 mmol of the yellow solid, 58%.

Compound 202 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 21C.

TABLE 21C Cd. Structure IUPAC Name [M + H]⁺ 202

N-(3,4-dimethoxyphenyl)-3- (7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 416.7

Example 21B Synthesis of Compound 203

Preparation oftrans-4-(3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of-chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50mg, 0.168 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (23 mg, 0.168 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.840 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 32 mg of the yellow solid, 48%.

Compound 203 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 21D.

TABLE 21D Cd. Structure IUPAC Name [M + H]⁺ 203

trans-4-(3-(7- methylbenzo[b]thiophen- 2-yl)imidazo]1,2- b]pyridazin-6-ylamino)cyclohexanol 379.4

Example 22 Synthesis of Compound 72

Preparation of6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 6-methoxybenzo[b]thiophen-2-yl-2-boronic acid (49 mg,0.237 mmol, 1.1 equiv) in acetonitrile (2.15 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (50 mg, 0.215 mmol, 1.0 equiv),palladium catalyst (8 mg, 0.0108 mmol, 0.05 equiv) and sodium carbonate(2.15 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave50 mg of the yellow solid, 75%.

Preparation of3-(6-methoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (82mg, 0.260 mmol, 1.0 equiv), xantphos (30 mg, 0.0519 mmol, 0.2 equiv),palladium acetate (6 mg, 0.0260 mmol, 0.1 equiv), and potassiumcarbonate (718 mg, 5.19 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (48 mg, 0.312 mmol, 1.1 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 77 mg, 0.195 mmol of the yellow solid, 75%.

Compound 72 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table22-b.

TABLE 22-b Cd. Structure IUPAC Name [M + H]⁺ 72

3-(6- methoxybenzo[b]thiophen-2- yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 395.1

Example 23 Synthesis of Compound 172

Preparation oftrans-4-(3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50mg, 0.111 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (30 mg, 0.111 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.803 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 33 mg of the yellow solid, 75%.

Compound 172 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 23-b.

TABLE 23-b Cd. Structure IUPAC Name [M + H]⁺ 172

trans-4-(3-(6- methoxybenzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 395.1

Example 24 Synthesis of Compound 167

Preparation of6-chloro-3-(5-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 6-methoxybenzo[b]thiophen-2-yl-2-boronic acid (50 mg,0.242 mmol, 1.1 equiv) in acetonitrile (2.15 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (56 mg, 0.220 mmol, 1.0 equiv),palladium catalyst (8 mg, 0.0121 mmol, 0.05 equiv) and sodium carbonate(2.42 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave50 mg of the yellow solid, 77%.

Preparation of3-(5-methoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (80mg, 0.254 mmol, 1.0 equiv), xantphos (29 mg, 0.0506 mmol, 0.2 equiv),palladium acetate (6 mg, 0.0254 mmol, 0.1 equiv), and potassiumcarbonate (700 mg, 5.06 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (47 mg, 0.304 mmol, 1.1 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 62 mg, 0.152 mmol of the yellow solid, 60%.

Compound 167 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 24-b.

TABLE 24-b Cd. Structure IUPAC Name [M + H]⁺ 167

3-(5- methoxybenzo[b]thiophen-2- yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 433.7

Example 25A Synthesis of Compound 168

Preparation oftrans-4-(3-(5-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(5-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (47mg, 0.151 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (29 mg, 0.151 mmol, 1.0 equiv) and amine (0.755 mmol,5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gave30 mg of the yellow solid, 50%.

Compound 168 weal physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 25A.

TABLE 25A Cd. Structure IUPAC Name [M + H]⁺ 168

trans-4-(3-(5- methoxybenzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 395.7

Example 25B Synthesis of Compound 191

Preparation of6-chloro-3-(5-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 6-methylbenzo[b]thiophen-2-yl-2-boronic acid (120 mg,0.627 mmol, 1.2 equiv) in acetonitrile (5.22 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (146 mg, 0.522 mmol, 1.0 equiv),palladium catalyst (38 mg, 0.0522 mmol, 0.1 equiv) and sodium carbonate(5.22 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave50 mg of the yellow solid 125 mg, 80%.

Preparation of3-(5-methylbenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50mg, 0.168 mmol, 1.0 equiv), xantphos (19 mg, 0.0334 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0167 mmol, 0.1 equiv), and potassiumcarbonate (461 mg, 3.34 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (28 mg, 0.167 mmol, 1.1 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 42 mg, 0.152 mmol of the yellow solid, 60%.

Compound 191 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 25B.

TABLE 25B Cd. Structure IUPAC Name [M + H]⁺ 191

N-(3,4-dimethoxyphenyl)-3- (5-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- amine 417.1

Example 25C Synthesis of Compound 192

Preparation oftrans-4-(3-(5-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(5-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50mg, 0.168 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (30 mg, 0.168 mmol, 1.0 equiv) and amine (0.840 mmol,5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 5% methanol in dichloromethane elution gave30 mg of the yellow solid, 47%.

Compound 192 weal physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 25C.

TABLE 25C Cd. Structure IUPAC Name [M + H]⁺ 192

trans-4-(3-(5- methylbenzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 379.5

Example 26 Synthesis of Compounds 67, 70-71

Preparation of6-chloro-3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 5,6-dimethoxybenzo[b]thiophen-2-yl-2-boronic acid (471mg, 1.98 mmol, 1.3 equiv) in acetonitrile (10.0 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (425 mg, 1.52 mmol, 1.0 equiv),palladium catalyst (56 mg, 0.0760 mmol, 0.05 equiv) and sodium carbonate(10.0 mL, 1.0 M, 10.0 equiv). The solution was stirred at rt overnight.Purification using column chromatography gave 368 mg of the product,70%: ¹H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.32 (d, J=7.6 Hz, 1H), 8.06(s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.44 (d, J=7.6 Hz, 1H), 3.85 (s,3H), 3.84 (s, 3H).

Preparation of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(69 mg, 0.20 mmol, 1.0 equiv), xantphos (23 mg, 0.04 mmol, 0.2 equiv),palladium acetate (4 mg, 0.02 mmol, 0.1 equiv), and potassium carbonate(553 mg, 4.00 mmol, 20 equiv) in dioxane (5.0 mL) was added amine (0.20mmol, 1.0 equiv) and heated to 110° C. for 2 h. Purification by columnchromatography using 2% methanol in dichloromethane elution gave theproduct.

TABLE 26-a Cd. Amine Pure Isolated Compound 67 3,4-dimethoxyaniline3-(5,6-dimethoxybenzo[b]thiophen- 2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 70 3-(4-amino-2-3-(4-(3-(5,6-dimethoxybenzo[b]thiophen- methoxyphenoxy)propan-2-yl)imidazo[1,2-b]pyridazin- 1-ol 6-ylamino)-2-methoxyphenoxy)propan-1-ol 71 methyl 3-aminobenzoate3-(3-(5,6-dimethoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6-ylamino)benzoic acid

Compounds 67, 70-71 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 26-b.

TABLE 26-b Cd. Structure IUPAC Name [M + H]⁺ 67

3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 463.5 70

3-(4-(3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6-ylamino)-2- methoxyphenoxy)propan-1-ol 507.3 71

3-(3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6-ylamino)benzoic acid 447.1

Example 27 Synthesis of Compound 75

Preparation of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)-N-methylimidazo[1,2-b]pyridazin-6-amine

To a solution of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine(50 mg, 0.108 mmol, 1.0 equiv) in DMF (5.0 mL) was added NaH (13 mg,0.324 mmol, 3.0 equiv) followed by iodomethane (0.07 mL, 0.541 mmol, 5.0equiv). After 1 h, the reaction was quenched with saturated aqueoussolution of ammonium chloride then extracted with ethyl acetate.Purification by column chromatography using 2% methanol indichloromethane elution gave 30 mg of the brown solid, 58%.

Compound 75 was physically characterized by electrospray ionization massspectrometry. Structure and molecular mass is given below in Table 27-b.

TABLE 27-b Cd. Structure IUPAC Name [M + H]⁺ 75

3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)-N-(3,4- dimethoxyphenyl)-N-methylimidazo[1,2- b]pyridazin-6-amine 477.1

Example 28 Synthesis of Compounds 69, 73-74

Preparation of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-6-arylimidazo[1,2-b]pyridazine

To a solution of6-chloro-3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(100 mg, 0.289 mmol, 1.0 equiv) in acetonitrile (5.0 mL) was addedboronic acid (0.376 mmol, 1.3 equiv), palladium catalyst (3 mg, 0.014mmol, 0.05 equiv) and sodium carbonate (2.89 mL, 1.0 M, 10.0 equiv). Thesolution was heated in the microwave at 150° C. for 10 minutes.Purification using column chromatography gave the product.

TABLE 28-a Cd. Boronic Acid Pure Isolated Compound 691H-indol-5-yl-5-boronic 6-(1H-indol-5-yl)-3-(5,6- aciddimethoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazine 734-((4-methylpiperazin-1- 3-(5,6-dimethoxybenzo[b]thiophen-2-yl)methyl)phenylboronic yl)-6-(4-((4-methylpiperazin-1- acidyl)methyl)phenyl)imidazo[1,2- b]pyridazine 74 3-((4-methylpiperazin-1-3-(5,6-dimethoxybenzo[b]thiophen-2- yl)methyl)phenylboronicyl)-6-(3-((4-methylpiperazin-1- acid yl)methyl)phenyl)imidazo[1,2-b]pyridazine

Compounds 69, 73-74 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 28-b.

TABLE 28-b Cd. Structure IUPAC Name [M + H]⁺ 69

6-(1H-indol-5-yl)-3-(5,6- dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine 427.0 73

3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)-6-(4-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazine 500.2 74

3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)-6-(3-((4- methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2- b]pyridazine 500.3

Example 29 Synthesis of Compounds 169, 171, 173-174

Preparation of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-alkylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(311 mg, 0.899 mmol, 1.0 equiv) in DMSO (5.0 mL) was added p-toluenesulfonic acid monohydrate (171 mg, 0.899 mmol, 1.0 equiv) and amine(4.50 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reactionmixture was diluted with water and extracted with ethyl acetate.Purification by column chromatography using 5% methanol indichloromethane elution gave the product.

TABLE 29-a Cd. Amine Pure Isolated Compound 169trans-4-aminocyclohexanol trans-4-(3-(5,6- dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 1714-amino-2-methylbutan- 4-(3-(5,6- 1-ol dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)-2-methylbutan-1-ol 173trans-4-amino-1- (1r,4r)-4-(3-(5,6- methylcyclohexanoldimethoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-1-methylcyclohexanol 174 3-aminocyclohexanol 3-(3-(5,6-dimethoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 201 trans-4- trans-3-(5,6- methoxycyclohexanaminedimethoxybenzo[b]thiophen-2- yl)-N-(4- methoxycyclohexyl)imidazo[1,2-b]pyridazin-6-amine

Compounds 169, 171, 173-174, 201 were physically characterized byelectrospray ionization mass spectrometry. Structures and molecularmasses are given below in Table 29-b.

TABLE 29-b Cd. Structure IUPAC Name [M + H]⁺ 169

trans-4-(3-(5,6- dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 425.5 171

4-(3-(5,6- dimethoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)-2-methylbutan-1-ol 413.3 173

(1r,4r)-4-(3-(5,6- dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6- ylamino)-1-methylcyclohexanol 439.2 174

3-(3-(5,6- dimethoxybenzo[b]thiophen-2- yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol 425.1 201

trans-3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)-N-(4-methoxycyclohexyl)imidazo[1,2- b]pyridazin-6-amine 439.4

Example 30 Synthesis of Compounds 175 and 177

Preparation of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-(trans-4-methoxycyclohexyl)-N-methylimidazo[1,2-b]pyridazin-6-amineandtrans-4-(N-(3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)-N-methylamino)cyclohexanol

To a solution oftrans-4-(3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol(100 mg, 0.236 mmol, 1.0 equiv) in DMF (2.00 mL) was added sodiumhydride (28 mg, 0.707 mmol, 3.0 equiv) and methyl iodide (167 mg, 1.18mmol, 5.0 equiv). After 2 h, the reaction mixture was quenched withwater and extracted with ethyl acetate. Purification by columnchromatography gave 30 mg (28%) of3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-(trans-4-methoxycyclohexyl)-N-methylimidazo[1,2-b]pyridazin-6-amineas the less polar product and 21 mg (20%) oftrans-4-(N-(3-(5,6-dimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)-N-methylamino)cyclohexanolas the more polar product.

Compounds 175 and 177 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 30-b.

TABLE 30-b Cd. Structure IUPAC Name [M + H]⁺ 175

3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)-N-(trans-4-methoxycyclohexyl)-N- methylimidazo[1,2- b]pyridazin-6-amine 453.3 177

trans-4-(N-(3-(5,6- dimethoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6-yl)-N- methylamino)cyclohexanol 439.4

Example 31 Synthesis of Compound 76

Preparation of O-ethyl S-3,4,5-trimethoxyphenyl carbonodithioate

Aniline (2.00 g, 10.9 mmol, 1.0 equiv) at 0° C. was added hydrochloricacid (3 mL) and water (10 mL) followed by sodium nitrite (932 mg, 13.5mmol, 1.25 equiv). The resulting solution was poured over potassiumethyl xanthogenate (5.35 g, 33.4 mmol, 3.0 equiv) in water (10 mL) andstirred at 50° C. for 40 minutes. Purification by column chromatographyusing 5% ethyl acetate in hexanes elution gave the yellow solid.

Preparation of 3,4,5-trimethoxybenzenethiol

To a solution of O-ethyl S-3,4,5-trimethoxyphenyl carbonodithioate (3.45g, 10.9 mmol, 1.0 equiv) in methanol (30 mL) was added sodium hydroxide(1.44 g, 32.8 mmol, 3.0 equiv) and heated to 60 C for 3 h. Purificationby column chromatography using 5% ethyl acetate in hexanes elution gave1.75 g, 8.73 mmol of the yellow solid, 80% over 2 steps.

Preparation of (2,2-diethoxyethyl)(3,4,5-trimethoxyphenyl)sulfane

To a solution of thiophenol (1.3 g, 6.49 mmol, 1.0 equiv) in acetone (20mL) was added potassium carbonate (1.79 g, 13.0 mmol, 2.0 equiv) andbromoacetaldehyde diethylacetal (2.56 g, 13.0 mmol, 2.0 equiv). After 15h, the reaction mixture was filtered and concentrated. Purification bycolumn chromatography using 5% ethyl acetate in hexanes elution gave theproduct.

Preparation of 4,5,6-trimethoxybenzo[b]thiophene

To a solution of thioether (1.00 g, 3.16 mmol, 1.0 equiv) in toluene (20mL) was added phosphoric acid (10 mL) and heated to 110° C. After 2 h,the reaction mixture was diluted with a saturated aqueous solution ofsodium bicarbonate and extracted with ethyl acetate then concentrated.Purification by column chromatography using 5% ethyl acetate in hexaneselution gave 230 g of the white product, 32% yield.

Preparation of 4,5,6-trimethoxybenzo[b]thiophen-2-yl-2-boronic acid

To a solution of 4,5,6-trimethoxybenzo[b]thiophene (200 mg, 0.892 mmol,1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (0.84 mL, 1.34mmol, 1.5 equiv). The reaction was stirred at the reduced temperaturefor 1 h, then triisopropylborate (0.31 mL, 1.34 mmol, 1.5 equiv) wasadded and stirred at rt for 2 h. The mixture was quenched with 2N HCland then extracted with ethyl acetate. Purification by columnchromatography using 2% methanol in dichloromethane elution gave 191 mgof white solid, 80%.

Preparation of6-chloro-3-(4,5,6-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 4,5,6-trimethoxybenzo[b]thiophen-2-yl-2-boronic acid(200 mg, 0.746 mmol, 1.3 equiv) in acetonitrile (10.0 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (160 mg, 0.574 mmol, 1.0 equiv),palladium catalyst (20 mg, 0.0287 mmol, 0.05 equiv) and sodium carbonate(5.74 mL, 1.0 M, 10.0 equiv). The solution was stirred at rt overnight.Purification using column chromatography gave 151 mg of the yellowproduct, 70%.

Preparation of3-(4,5,6-trimethoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(4,5,6-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(50 mg, 0.133 mmol, 1.0 equiv), xantphos (15 mg, 0.0266 mmol, 0.2equiv), palladium acetate (2 mg, 0.0133 mmol, 0.1 equiv), and potassiumcarbonate (367 mg, 2.66 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (20 mg, 0.133 mmol, 1.0 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave the product.

Compound 76 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table32-b.

TABLE 32-b Cd. Structure IUPAC Name [M + H]⁺ 76

3-(4,5,6- trimethoxybenzo[b]thiophen- 2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 493.3

Example 33 Synthesis of Compound 176

Preparation oftrans-4-(3-(4,5,6-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(4,5,6-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(50 mg, 0.133 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (25 mg, 0.144 mmol, 1.0 equiv) and amine(0.532 mmol, 4.0 equiv) and heated to 100° C. for 24 h. The reactionmixture was diluted with water and extracted with ethyl acetate.Purification by column chromatography using 5% methanol indichloromethane elution 40 mg of the brown solid, 67%.

Compound 176 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 33-b.

Cd. Structure IUPAC Name [M + H]⁺ 176

trans-4-(3-(4,5,6, trimethoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 455.4

Example 34 Synthesis of Compound 83

Preparation of O-ethyl S-2,3,4-trimethoxyphenyl carbonodithioate

Aniline (482 g, 2.63 mmol, 1.0 equiv) at 0° C. was added hydrochloricacid (0.71 mL) and water (1.86 mL) followed by sodium nitrite (227 mg,3.29 mmol, 1.25 equiv). The resulting solution was poured over potassiumethyl xanthogenate (1.31 g, 8.06 mmol, 3.0 equiv) in water (1.50 mL) andstirred at 50° C. for 40 minutes. Purification by column chromatographyusing 5% ethyl acetate in hexanes elution gave the yellow solid.

Preparation of 2,3,4-trimethoxybenzenethiol

To a solution of O-ethyl S-2,3,4-trimethoxyphenyl carbonodithioate (759mg, 2.63 mmol, 1.0 equiv) in methanol (10 mL) was added sodium hydroxide(347 mg, 7.89 mmol, 3.0 equiv) and heated to 60 C for 3 h. Purificationby column chromatography using 5% ethyl acetate in hexanes elution gave395 mg of the yellow solid, 75% over 2 steps.

Preparation of (2,2-diethoxyethyl)(2,3,4-trimethoxyphenyl)sulfane

To a solution of thiophenol (1.02 g, 5.09 mmol, 1.0 equiv) in acetone(20 mL) was added potassium carbonate (1.41 g, 10.2 mmol, 2.0 equiv) andbromoacetaldehyde diethylacetal (1.57 g, 10.2 mmol, 2.0 equiv). After 15h, the reaction mixture was filtered and concentrated. Purification bycolumn chromatography using 5% ethyl acetate in hexanes elution gave theproduct.

Preparation of 5,6,7-trimethoxybenzo[b]thiophene

To a solution of thioether (1.03 g, 3.25 mmol, 1.0 equiv) in toluene (20mL) was added phosphoric acid (10 mL) and heated to 110° C. After 2 h,the reaction mixture was diluted with a saturated aqueous solution ofsodium bicarbonate and extracted with ethyl acetate then concentrated.Purification by column chromatography using 5% ethyl acetate in hexaneselution gave 300 mg of the white solid, 41%.

Preparation of 5,6,7-trimethoxybenzo[b]thiophen-2-yl-2-boronic acid

To a solution of 5,6,7-trimethoxybenzo[b]thiophene (365 mg, 1.62 mmol,1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (1.53 mL, 2.44mmol, 1.5 equiv). The reaction was stirred at the reduced temperaturefor 1 h, then triisopropylborate (0.56 mL, 2.44 mmol, 1.5 equiv) wasadded and stirred at rt for 2 h. The mixture was quenched with 2N HCland then extracted with ethyl acetate. Purification by columnchromatography using 2% methanol in dichloromethane elution gave 370 mgof white solid, 85%.

Preparation of6-chloro-3-(5,6,7-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 5,6,7-trimethoxybenzo[b]thiophen-2-yl-2-boronic acid(410 mg, 1.53 mmol, 1.3 equiv) in acetonitrile (10 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (427 mg, 1.53 mmol, 1.0 equiv),palladium catalyst (56 mg, 0.077 mmol, 0.05 equiv) and sodium carbonate(15.3 mL, 1.0 M, 10.0 equiv). The solution was stirred in the microwaveat 150° C. for 10 min. Purification using column chromatography gave 368mg of the yellow product, 64%.

Preparation of3-(5,6,7-trimethoxybenzo[b]thiophen-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5,6,7-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(50 mg, 0.133 mmol, 1.0 equiv), xantphos (15 mg, 0.0266 mmol, 0.2equiv), palladium acetate (2 mg, 0.0133 mmol, 0.1 equiv), and potassiumcarbonate (367 mg, 2.66 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (20 mg, 0.133 mmol, 1.0 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave the product.

Compound 83 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table34-b.

TABLE 34 Cd. Structure IUPAC Name [M + H]⁺ 83

3-(5,6,7- trimethoxybenzo[b]thiophen- 2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 492.9

Example 35 Synthesis of Compound 179

Preparation oftrans-4-(3-(5,6,7-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(5,6,7-trimethoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(50 mg, 0.133 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (25 mg, 0.144 mmol, 1.0 equiv) and amine(0.532 mmol, 4.0 equiv) and heated to 100° C. for 24 h. The reactionmixture was diluted with water and extracted with ethyl acetate.Purification by column chromatography using 5% methanol indichloromethane elution 36 mg of the brown solid, 60%.

Compound 179 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 35-b.

TABLE 35-b Cd. Structure IUPAC Name [M + H]⁺ 179

trans-4-(3-(5,6,7- trimethoxybenzo[b]thiophen- 2-yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 455.0

Example 36 Synthesis of Compounds 94-96, 99, 104

Preparation of 6-chloro-3-arylimidazo[1,2-b]pyridazine

To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (1.55 g, 10.1mmol) in 10.0 mL of toluene was added aryl bromide (15.1 mmol, 1.5equiv), potassium carbonate (2.79 g, 18.2 mmol, 2.0 equiv),triphenylphosphine (529 mg, 2.02 mmol, 0.2 equiv) and palladium acetate(227 mg, 1.01 mmol, 0.1 equiv). The solution was stirred to reflux for24 h. Purification by column chromatography using 50% ethyl acetate inhexanes elution gave the product.

Preparation of N-alkyl-3-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-arylimidazo[1,2-b]pyridazine (0.500 mmol,1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acidmonohydrate (95 mg, 0.500 mmol, 1.0 equiv) and amine (1.95 mmol, 4.0equiv) and heated to 100° C. for 24 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. Purification by columnchromatography using 5% methanol in dichloromethane elution gave theproduct.

TABLE 3a Cd. Aryl bromide Amine Pure Isolated Compound  94 BromobenzeneMethyl amine N-methyl-3-phenylimidazo[1,2-b]pyridazin- 6-amine  951-bromo-4- Methyl amine 3-(4-methoxyphenyl)-N-methylimidazo[1,2-methoxybenzene b]pyridazin-6-amine  96 1-bromo-2- Methyl amine3-(2-methoxyphenyl)-N-methylimidazo[1,2- methoxybenzeneb]pyridazin-6-amine  99 1-bromo-3- Methyl amine3-(3-methoxyphenyl)-N-methylimidazo[1,2- methoxybenzeneb]pyridazin-6-amine 104 5-bromo-1,2,3- trans-4-trans-4-(3-(3,4,5-trimethoxyphenyl)imidazo[1, trimethoxybenzeneaminocyclohexanol 2-b]pyridazin-6-ylamino)cyclohexanol

Compounds 94-96, 99, 104 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 36-b.

TABLE 36-b Cd. Structure IUPAC Name [M + H]⁺ 94

N-methyl-3-phenylimidazo[1,2- b]pyridazin-6-amine 225.5 95

3-(4-methoxyphenyl)-N- methylimidazo[1,2-b]pyridazin-6- amine 255.6 96

3-(2-methoxyphenyl)-N- methylimidazo[1,2-b]pyridazin-6- amine 255.5 99

3-(3-methoxyphenyl)-N- methylimidazo[1,2-b]pyridazin-6- amine 255.6 104

trans-4-(3-(3,4,5 trimethoxyphenyl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 399.5

Example 37 Synthesis of Compounds 97-98, 100-102

Preparation of 3-(hydroxyphenyl)-N-alkylimidazo[1,2-b]pyridazin-6-amine

To a solution of 3-(alkoxyphenyl)-N-alkylimidazo[1,2-b]pyridazin-6-amine(0.197 mmol, 1.0 equiv) in dichloromethane at −78° C. was added borontribromide (0.10 mL, 1.0 M solution in dichloromethane, 5.4 equiv). Thereaction mixture was stirred at the reduced temperature for 10 min thenwarmed to room temperature and stirred for 15 h. Methanol (2 mL) wasadded to quench the reaction and extracted with dichloromethane.Purification by column chromatography using 5% methanol indichloromethane elution gave the product.

TABLE 37-a Cd. Aryl bromide Amine Pure Isolated Compound  97 1-bromo-4-Methyl amine 4-(6-(methylamino)imidazo[1,2-b]pyridazin- methoxybenzene3-yl)phenol  98 1-bromo-2- Methyl amine2-(6-(methylamino)imidazo[1,2-b]pyridazin- methoxybenzene 3-yl)phenol100 1-bromo-3- Methyl amine 3-(6-(methylamino)imidazo[1,2-b]pyridazin-methoxybenzene 3-yl)phenol 101 1-bromo-3- trans-4-trans-3-(6-(4-hydroxy- methoxybenzene aminocyclohexanolcyclohexylamino)imidazo[1,2-b]pyridazin-3-yl)phenol 102 1-bromo-4-trans-4- trans-4-(3-(3,4,5-trimethoxyphenyl)imidazo[1,2- methoxybenzeneaminocyclohexanol b]pyridazin-6-ylamino)cyclohexanol

Compounds 97-98, 100-102 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 37-b.

TABLE 37-b Cd. Structure IUPAC Name [M + H]⁺ 97

4-((6-(methylamino)imidazol[1,2- b]pyridazin-3-yl)phenol 241.6 98

2-(6-(methylamino)imidazo[1,2- b]pyridazin-3-yl)phenol 241.5 100

3-(6-(methylamino)imidazo[1,2- b]pyridazin-3-yl)phenol 241.6 101

trans-3-(6-(4- hydroxycyclohexylamino)imidazo[1,2-b]pyridazin-3-yl)phenol 325.7 102

trans-4-(6-(4- hydroxycyclohexylamino)imidazo[1,2-b]pyridazin-3-yl)phenol 525.7

Example 38 Synthesis of Compound 66

Preparation of3-(5-fluorobenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (118 mg,0.338 mmol, 1.0 equiv) in acetonitrile (3.38 mL) was added2-(5-fluorobenzo[b]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(122 mg, 0.439 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II)dichloride (24 mg, 0.0338 mmol, 0.1 equiv), then sodium carbonate (3.38mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture wasirradiated in the microwave at 150° C. for 10 min. Purification bycolumn chromatography gave 100 mg of the brown solid, 70%.

Compound 66 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table38-b.

TABLE 38 Cd. Structure IUPAC Name [M + H]⁺ 66

3-(5-fluorobenzo[b]thiophen-2-yl)- N-(3,4- dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine 421.8

Example 39 Synthesis of Compound 166 Scheme 39 Preparation oftrans-4-(3-bromoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To 6-chloro-3-bromoimidazo[1,2-b]pyridazine (1.00 g, 4.30 mmol, 1.0equiv) and p-TSA (818 mg, 4.30 mmol, 1.0 equiv) in DMSO (7.00 mL) wasadded trans-4-aminocyclohexanol (1.49 g, 12.9 mmol, 3.0 equiv). Themixture was heated at 100° C. for 24 h. Purification by columnchromatography using 5% methanol in dichloromethane elution gave 1.1 gof the yellow solid, 83%.

Preparation oftrans-4-(3-(5-fluorobenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (118 mg,0.338 mmol, 1.0 equiv) in acetonitrile (3.79 mL) was added2-(5-fluorobenzo[b]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(158 mg, 0.569 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II)dichloride (27 mg, 0.0379 mmol, 0.1 equiv), then sodium carbonate (3.79mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture wasirradiated in the microwave at 150° C. for 10 min. Purification bycolumn chromatography gave 90 mg of the yellow solid, 62%.

Compound 166 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 39-b.

TABLE 39-b Cd. Structure IUPAC Name [M + H]⁺ 166

trans-4-(3-(5- fluorobenzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 383.7

Example 40 Synthesis of Compound 84

Preparation of5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde

To a solution of 6-chloroimidazo[1,2-b]pyridazine (1.55 g, 10.1 mmol,1.0 equiv) in toluene (10.0 mL) was added5-bromothiophene-2-carbaldehyde (1.80 mL, 15.1 mmol, 1.5 equiv),potassium carbonate (2.79 g, 20.2 mmol, 2.0 equiv), triphenyl phosphine(529 mg, 2.02 mmol, 0.2 equiv) and potassium acetate (227 mg, 1.01 mmol,0.1 equiv). The reaction mixture was heated to reflux for 24 h thendiluted with water and extracted with ethyl acetate. Purification bycolumn chromatography using 50% ethyl acetate in hexanes elution gave1.60 g of the white solid, 60%.

Preparation of5-(6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde

To a solution of5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde (200mg, 0.758 mmol, 1.0 equiv), xantphos (88 mg, 0.152 mmol, 0.2 equiv),palladium acetate (17 mg, 0.0758 mmol, 0.1 equiv), and potassiumcarbonate (2.10 g, 1.52 mmol, 20 equiv) in dioxane (6.0 mL) was added3,4-dimethoxyaniline (116 mg, 0.758 mmol, 1.0 equiv) and heated to 100°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave the 100 mg of the brown solid, 35%.

Preparation of(5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl)methanol

To a solution of5-(6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde(34 mg, 0.0894 mmol, 1.0 equiv) in methanol (5.00 mL) was added sodiumborohydride (100 mg, 2.64 mmol, 30.0 equiv). After 1 h, the reactionmixture was quenched with water and extracted with ethyl acetate.Purification by column chromatography using 2% methanol in hexaneselution gave 20 mg of the brown solid, 58%.

Compound 84 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table40-b.

TABLE 40-b Cd. Structure IUPAC Name [M + H]⁺ 84

(5-(6-(3,4- dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)thiophen-2- yl)methanol 383.5

Example 41 Synthesis of Compound 92

Preparation oftrans-4-(3-(7-methoxybenzo[b]thiophen-4-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution oftrans-4-(3-bromoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol (45 mg,0.145 mmol, 1.0 equiv) in acetonitrile (1.45 mL) was added2-(7-methoxybenzo[b]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(55 mg, 0.188 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II)dichloride (11 mg, 0.0159 mmol, 0.1 equiv), then sodium carbonate (1.45mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture wasirradiated in the microwave at 150° C. for 10 min. Purification bycolumn chromatography gave 31 mg of the yellow solid, 53%.

Compound 92 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table41-b.

TABLE 41 Cd. Structure IUPAC Name [M + H]⁺ 92

trans-4-(3-(7- methoxybenzo[b]thiophen- 4-yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 395.0

Example 42 Synthesis of Compound 93

Preparation of3-(7-methoxybenzo[b]thiophen-4-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine

To a solution of 33-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (43 mg,0.123 mmol, 1.0 equiv) in acetonitrile (1.23 mL) was added2-(7-methoxybenzo[b]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(46 mg, 0.160 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II)dichloride (9 mg, 0.0123 mmol, 0.1 equiv), then sodium carbonate (1.23mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture wasirradiated in the microwave at 150° C. for 10 min. Purification bycolumn chromatography gave 30 mg of the yellow solid, 56%.

Compound 93 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table42-b.

TABLE 42 Cd. Structure IUPAC Name [M + H]⁺ 93

3-(7- methoxybenzo[b]thiophen-4- yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2- b]pyridazin-6-amine 433.1

Example 43 Synthesis of Compound 90

Preparation oftrans-4-(3-(benzo[b]thiophen-3-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution oftrans-4-(3-bromoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol (50 mg,0.159 mmol, 1.0 equiv) in acetonitrile (1.59 mL) was addedbenzo[b]thiophen-3-yl-3-boronic acid (117 mg, 0.239 mmol, 1.5 equiv),bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.0159 mmol, 0.1equiv), then sodium carbonate (1.59 mL, 1.0 M aqueous solution, 10equiv). The reaction mixture was irradiated in the microwave at 150° C.for 10 min. Purification by column chromatography gave 20 mg of theyellow solid, 36%.

Compound 90 was physically characterized by electrospray ionization massspectrometry. Structures and molecular masses are given below in Table43-b.

TABLE 43-b Cd. Structure IUPAC Name [M + H]⁺ 90

trans-4-(3- (benzo[b]thiophen-3- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 365.8

Example 44 Synthesis of Compound 91 and 180

Preparation of 6-chloro-3-(thiophen-3-yl)imidazo[1,2-b]pyridazine

To a solution of 6-chloroimidazo[1,2-b]pyridazine (200 mg, 1.30 mmol,1.0 equiv) in toluene (5.00 mL) was added 3-bromothiophene (0.18 mL,1.95 mmol, 1.5 equiv), potassium carbonate (360 mg, 2.60 mmol, 2.0equiv), triphenyl phosphine (68 mg, 0.260 mmol, 0.20 equiv) andpotassium acetate (29 mg, 0.130 mmol, 0.1 equiv). The reaction mixturewas heated to reflux for 24 h. Purification by column chromatographyusing 50% ethyl acetate in hexanes elution gave 201 mg of the whitesolid, 85%.

Preparation of N-alkyl-3-(thiophen-3-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of 6-chloro-3-(thiophen-3-yl)imidazo[1,2-b]pyridazine (299mg, 1.30 mmol, 1.0 equiv) in DMSO (5.00 mL) was added p-TSA (247 mg,1.30 mmol, 1.0 equiv) and amine (6.50 mmol, 5.0 equiv) and heated to100° C. for 24 h. Purification by column chromatography using 5%methanol in hexanes elution gave the product.

Compounds 91 and 180 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 44-b.

TABLE 44-b Cd. Amine Structure IUPAC Name [M + H]⁺  91 Methylamine

N-methyl-3- (thiophen-3- yl)imidazo[1,2- b]pyridazin-6-amine 231.6 180trans-4- aminocyclohexanol

trans-(3-(thiophen-3- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 315.6

Example 45 Synthesis of Compound 120

Preparation of 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine

To a solution of 6-chloro-4,5-dimethylpyridazin-3-amine (2.00 g, 12.7mmol, 1.0 equiv) in isopropanol (40 mL) was added bromoacetaldehydediethyl acetal (5.23 mL, 34.8 mmol, 2.7 equiv), and hydrobromic acid(2.00 mL) and heated to reflux for 2 h. The reaction mixture was dilutedwith saturated aqueous sodium bicarbonate and extracted with ethylacetate. Purification by column chromatography using 20% ethyl acetatein hexanes elution gave 2.07 g of the white solid, 90%.

Preparation of3-(benzo[b]thiophen-2-yl)-6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine

To a solution of 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine (162 mg,0.892 mmol, 1.0 equiv) in toluene (5.00 mL) was added2-bromobenzo[b]thiophene (213 mg, 1.16 mmol, 1.3 equiv), potassiumcarbonate (247 mg, 1.78 mmol, 2.0 equiv), triphenyl phosphine (47 mg,0.178 mmol, 0.20 equiv) and potassium acetate (20 mg, 0.0892 mmol, 0.1equiv). The reaction mixture was heated to reflux for 24 h. Purificationby column chromatography using 50% ethyl acetate in hexanes elution gave105 mg of the white solid, 38%.

Preparation of3-(benzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-6-amine

To a solution of3-(benzo[b]thiophen-2-yl)-6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine(89 mg, 0.284 mmol, 1.0 equiv), xantphos (33 mg, 0.0567 mmol, 0.2equiv), palladium acetate (6 mg, 0.0284 mmol, 0.1 equiv), and potassiumcarbonate (784 mg, 5.67 mmol, 20 equiv) in dioxane (5.00 mL) was added3,4-dimethoxyaniline (52 mg, 0.340 mmol, 1.0 equiv) and heated to 100°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave the 60 mg of the brown solid, 49%.

Compound 120 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 45-b.

TABLE 45-b Cd. Structure IUPAC Name [M + H]⁺ 120

3-(benzo[b]thiophen- 2-yl)-N-(3,4- dimethoxyphenyl)- 7,8-dimethylimidazo[1,2- b]pyridazin-6-amine 431.7

Example 46 Synthesis of Compound 121

Preparation oftrans-4-(3-(benzo[b]thiophen-2-yl)-7,8-dimethylimidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of3-(benzo[b]thiophen-2-yl)-6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine(40 mg, 0.128 mmol, 1.0 equiv) in DMSO (1.00 mL) was added p-TSA (24 mg,0.128 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (73 mg, 0.638 mmol,5.0 equiv) and heated to 100° C. for 24 h. Purification by columnchromatography using 5% methanol in dichloromethane elution gave 31 mg,62%.

Compound 121 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 46-b.

TABLE 46-b Cd. Structure IUPAC Name [M + H]⁺ 121

trans-4-(3- (benzo[b]thiophen-2- yl)-7,8- dimethylimidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 393.7

Example 47 Synthesis of Compounds 118 and 164

Preparation of6-chloro-3-(5-chloro-3-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of 6-chloroimidazo[1,2-b]pyridazine (606 mg, 3.95 mmol,1.0 equiv) in toluene (10.00 mL) was added2-bromo-5-chloro-3-methylbenzo[b]thiophene (1.03 g, 3.95 mmol, 1.0equiv), potassium carbonate (1.09 g, 7.90 mmol, 2.0 equiv), triphenylphosphine (207 mg, 0.790 mmol, 0.20 equiv) and potassium acetate (89 mg,0.395 mmol, 0.1 equiv). The reaction mixture was heated to reflux for 24h. Purification by column chromatography using 50% ethyl acetate inhexanes elution gave 500 mg of the white solid, 38%.

Preparation of3-(5-chloro-3-methylbenzo[b]thiophen-2-yl)-N-alkylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(5-chloro-3-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine(40 mg, 0.120 mmol, 1.0 equiv) in DMSO (1.00 mL) was added p-TSA (35 mg,0.120 mmol, 1.5 equiv) and amine (2.24 mmol, 12.5 equiv) and heated to100° C. for 24 h. Purification by column chromatography using 5%methanol in dichloromethane elution gave the product.

Compounds 118 and 164 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 47-b.

TABLE 47-b Cd. Amine Structure IUPAC [M + H]⁺ 118 4-aminobutan- 1-ol

4-(3-(5-chloro-3- methylbenzo[b]thio- phen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)butan-l-ol 387.6 164 trans-4- aminocyclohexanol

trans-4-(3-(5- chloro-3- methylbenzo[b]thio- phen-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 413.8

Example 48 Synthesis of Compound 165

Preparation of4-(3-(3-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol

To a solution of4-(3-(5-chloro-3-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol(20 mg, 0.0517 mmol, 1.0 equiv) in methanol (2.00 mL) was added Pd/C andplaced under a balloon of hydrogen. After 3 h, the reaction mixture wasfiltered through a plug of silica gel to provide 15 mg of the whitesolid, 82%.

Compound 165 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 48-b.

TABLE 48-b Cd. Structure IUPAC Name [M + H]⁺ 165

4-(3-(3- methylbenzo[b]thiophen- 2-yl)imidazo[1,2- b]pyridazin-6-ylamino)butan-l-ol 355.7

Example 49 Synthesis of Compound 204

Preparation of6-chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine

To a solution of thieno[2,3-b]pyridin-2-yl-2-boronic acid (304 mg, 1.70mmol, 1.1 equiv) in acetonitrile (14.2 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (396 mg, 1.42 mmol, 1.0 equiv),palladium catalyst (104 mg, 0.142 mmol, 0.1 equiv) and sodium carbonate(14.2 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave350 mg of the yellow solid, 86%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-(thieno[2,3-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (58mg, 0.202 mmol, 1.0 equiv), xantphos (23 mg, 0.0405 mmol, 0.2 equiv),palladium acetate (5 mg, 0.0202 mmol, 0.1 equiv), and potassiumcarbonate (559 mg, 4.05 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (37 mg, 0.247 mmol, 1.2 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 42 mg, 0.195 mmol of the yellow solid, 52%.

Compound 204 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable x.

TABLE 49 Cd. Structure IUPAC Name [M + H]⁺ 204

N-(3,4-dimethoxyphenyl)-3- (thieno[2,3-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6- amine 404.3

Example 50 Synthesis of Compound 205

Preparation oftrans-4-(3-(thieno[2,3-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(thieno[2,3-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (45 mg,0.157 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (22 mg, 0.157 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.784 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 40 mg of the yellow solid, 70%.

Compound 205 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 50.

TABLE x Cd. Structure IUPAC Name [M + H]⁺ 205

trans-4-(3-(thieno[2,3- b]pyridin-2- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 366.2

Example 51 Synthesis of Compound 218

Preparation of6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

To a solution of thieno[2,3-c]pyridin-2-yl-2-boronic acid (265 mg, 1.48mmol, 1.0 equiv) in acetonitrile (14.8 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (414 mg, 1.48 mmol, 1.0 equiv),palladium catalyst (108 mg, 0.148 mmol, 0.1 equiv) and sodium carbonate(14.8 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave200 mg of the white solid, 47%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg,0.174 mmol, 1.0 equiv), xantphos (20 mg, 0.0349 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0174 mmol, 0.1 equiv), and potassiumcarbonate (482 mg, 3.49 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (35 mg, 0.227 mmol, 1.3 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 38 mg, of the yellow solid, 54%.

Compound 218 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 51.

TABLE 51 Cd. Structure IUPAC Name [M + H]⁺ 218

N-(3,4-dimethoxyphenyl)-3- (thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6- amine 404.5

Example 52 Synthesis of Compound 219

Preparation oftrans-4-(3-(thieno[2,3-e]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg,0.174 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (25 mg, 0.174 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.870 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 42 mg of the yellow solid, 67%.

Compound 219 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 52.

TABLE 52 Cd. Structure IUPAC Name [M + H]⁺ 219

trans-4-(3-(thieno[2,3- c]pyridin-2- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 366.7

Example X Synthesis of Compound 206

Preparation of6-chloro-3-(thieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

To a solution of thieno[3,2-c]pyridin-2-yl-2-boronic acid (104 mg, 0.580mmol, 1.1 equiv) in acetonitrile (5.28 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (148 mg, 0.528 mmol, 1.0 equiv),palladium catalyst (39 mg, 0.0529 mmol, 0.1 equiv) and sodium carbonate(5.28 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave101 mg of the yellow solid, 67%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution ofN-(3,4-dimethoxyphenyl)-3-(thieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine(44 mg, 0.153 mmol, 1.0 equiv), xantphos (18 mg, 0.0306 mmol, 0.2equiv), palladium acetate (3 mg, 0.0153 mmol, 0.1 equiv), and potassiumcarbonate (424 mg, 3.07 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (28 mg, 0.184 mmol, 1.2 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 38 mg, of the yellow solid, 62%.

Compound 206 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 52.

TABLE 52 Cd. Structure IUPAC Name [M + H]⁺ 206

N-(3,4-dimethoxyphenyl)-3- (thieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6- amine 404.1

Example 53 Synthesis of Compound 207

Preparation oftrans-(3-(thieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(thieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg,0.174 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (25 mg, 0.174 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.870 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 40 mg of the yellow solid, 63%.

Compound 207 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 53.

TABLE 53 Cd. Structure IUPAC Name [M + H]⁺ 207

trans-(3-(thieno[3,2- c]pyridin-2- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 366.5

Example 54 Synthesis of Compound 208

Preparation of6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine

To a solution of thieno[3,2-b]pyridin-2-yl-2-boronic acid (104 mg, 0.580mmol, 1.1 equiv) in acetonitrile (5.28 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (148 mg, 0.528 mmol, 1.0 equiv),palladium catalyst (39 mg, 0.0529 mmol, 0.1 equiv) and sodium carbonate(5.28 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in themicrowave for 10 minutes. Purification using column chromatography gave95 mg of the yellow solid, 63%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg,0.174 mmol, 1.0 equiv), xantphos (20 mg, 0.0348 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0174 mmol, 0.1 equiv), and potassiumcarbonate (482 mg, 3.49 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (32 mg, 0.209 mmol, 1.2 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 35 mg, of the yellow solid, 50%.

Compound 208 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 54.

TABLE 54 Cd. Structure IUPAC Name [M + H]⁺ 208

N-(3,4-dimethoxyphenyl)-3- (thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6- amine 404.5

Example 55 Synthesis of Compound 209 Scheme 55

Preparation oftrans-4-(3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (40 mg,0.139 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonicacid monohydrate (20 mg, 0.139 mmol, 1.0 equiv) andtrans-4-aminocyclohexanol (0.695 mmol, 5.0 equiv) and heated to 100° C.for 24 h. The reaction mixture was diluted with water and extracted withethyl acetate. Purification by column chromatography using 5% methanolin dichloromethane elution gave 40 mg of the yellow solid, 79%.

Compound 209 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 55.

TABLE 55 Cd. Structure IUPAC Name [M + H]⁺ 209

trans-4-(3-(thieno[3,2- b]pyridin-2- yl)imidazo[1,2- b]pyridazin-6-ylamino)cyclohexanol 366.5

Example 56 Synthesis of Compound 210

Preparation of thieno[3,2-c]pyridin-7(6H)-one

To a solution of 5,6-dihydro-5-tosylthieno[3,2-c]pyridin-7(4H)-one (1.24g, 4.03 mmol, 1.0 equiv) in HOt-Bu (15.0 mL) was added KOt-Bu (904 mg,8.06 mmol, 2.0 equiv) and heated to reflux for 2 h. The mixture wasquenched with water and then extracted with ethyl acetate. Purificationby column chromatography using 50% ethyl acetate in hexanes elution gave1.09 g of white solid, 89%.

Preparation of thieno[3,2-c]pyridin-7-yl 4-methylbenzenesulfonate

To a solution of thieno[3,2-c]pyridin-7(6H)-one (110 mg, 0.728 mmol, 1.0equiv) in THF (5.00 mL) was added NaH (35 mg, 0.873 mmol, 1.2 equiv)followed by TsCl (180 mg, 0.946 mmol, 1.3 equiv). The reaction mixturewas stirred at rt for 2 h, then quenched with water and extracted withethyl acetate. Purification by column chromatography using 20% ethylacetate in hexanes elution gave 180 mg of a white solid, 81%.

Preparation of7-(4-methylbenzenesulfonyl)thieno[3,2-c]pyridin-2-yl-2-boronic acid

To a solution of thieno[3,2-c]pyridin-7-yl 4-methylbenzenesulfonate(1.18 g, 3.86 mmol, 1.0 equiv) in THF (20.0 mL) at −78° C. was addedn-BuLi (3.62 mL, 5.80 mmol, 1.5 equiv). The reaction was stirred at thereduced temperature for 1 h, then triisopropylborate (1.34 mL, 5.80mmol, 1.5 equiv) was added and stirred at rt for 2 h. The mixture wasquenched with 2N HCl and then extracted with ethyl acetate. Purificationby column chromatography using 2% methanol in dichloromethane elutiongave 800 mg of white solid, 59%.

Preparation of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-yl4-methylbenzenesulfonate

To a solution of7-(4-methylbenzenesulfonyl)thieno[3,2-c]pyridin-2-yl-2-boronic acid (650mg, 1.69 mmol, 1.1 equiv) in acetonitrile (16 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (473 mg, 1.69 mmol, 1.0 equiv),palladium catalyst (124 mg, 0.169 mmol, 0.1 equiv) and sodium carbonate(16.9 mL, 1.0 M, 10.0 equiv). The solution was stirred in the microwaveat 150° C. for 10 min. Purification using column chromatography gave 600mg of the yellow product, 78%.

Preparation of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol

To a solution of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-yl4-methylbenzenesulfonate (200 mg, 0.349 mmol, 1.0 equiv) in MeOH (5.0mL) was added sodium hydroxide (70 microliter, 5.0 M aqueous solution,1.0 equiv). The reaction mixture was stirred at rt for 3 h, thenquenched with water and extracted with ethyl acetate. Purification usingcolumn chromatography gave 80 mg of the white product, 76%.

Preparation of6-chloro-3-(7-methoxythieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

To a solution of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol (38mg, 0.126 mmol, 1.0 equiv) in DCM (3.0 mL) and MeOH (1.0 mL) was addedDIPEA (0.188 mmol, 1.5 equiv) then TMSCHN₂ (94 microliter, 0.188 mmol,1.5 equiv). The reaction mixture was stirred at rt for 3 h, thenquenched with water and extracted with ethyl acetate. Purification bycolumn chromatography using 20% ethyl acetate in hexanes elution gave 20mg of the yellow solid, 50%.

Preparation of3-(7-methoxythieno[3,2-c]pyridin-2-yl)-N-arylimidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methoxythieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(30 mg, 0.095 mmol, 1.0 equiv), xantphos (11 mg, 0.0189 mmol, 0.2equiv), palladium acetate (2 mg, 0.0947 mmol, 0.1 equiv), and potassiumcarbonate (261 mg, 1.89 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (22 mg, 0.142 mmol, 1.5 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 28 mg, of the yellow solid, 68%.

Compound 210 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 56.

Cd. Structure IUPAC Name [M + H]⁺ 210

N-(3,4-dimethoxyphenyl)-3- (7-methoxythieno[3,2-c]pyridin-2-yl)imidazo[1,2- b]pyridazin-6-amine 434.0

Example 57 Synthesis of Compound 211

Preparation of2-(6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol

To a solution of2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol (50mg, 0.165 mmol, 1.0 equiv), xantphos (19 mg, 0.0330 mmol, 0.2 equiv),palladium acetate (4 mg, 0.0165 mmol, 0.1 equiv), and potassiumcarbonate (456 mg, 3.30 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (38 mg, 0.248 mmol, 1.5 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 30 mg, of the brown solid, 43%.

Compound 211 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 57.

Cd. Structure IUPAC Name [M + H]⁺ 211

2-(6-(3,4- dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)thieno[3,2- c]pyridin-7-ol 420.5

Example 58 Synthesis of Compound 212

Preparation ofN-(3,4-dimethoxyphenyl)-3-(7-methoxythieno[3,2-c]pyridin-2-yl)-N-methylimidazo[1,2-b]pyridazin-6-amine

To a solution of2-(6-(3,4-dimethoxyphenylamino)imidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol(10 mg, 0.0238 mmol, 1.0 equiv) in THF (3.00 mL) was added NaH (30 mg,0.750 mol, 31.5 equiv) then iodomethane (100 mg, 0.705 mmol, 30.0equiv). The reaction mixture was stirred at rt for 2 h. Purification bycolumn chromatography using 2% methanol in dichloromethane elution gave10 mg, of the yellow solid, 94%.

Compound 212 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 58.

58. Structure IUPAC Name [M + H]⁺ 212

N-(3,4-dimethoxyphenyl)-3- (7-methoxythieno[3,2- c]pyridin-2-yl)-N-methylimidazo[1,2- b]pyridazin-6-amine 448.1

Example X Synthesis of Compound 213, 217

Preparation ofN-Alkyl-3-(7-methoxythieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methoxythieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(20 mg, 0.0631 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (12 mg, 0.0631 mmol, 1.0 equiv) and amine (36mg, 0.316 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reactionmixture was diluted with water and extracted with ethyl acetate.Purification by column chromatography using 5% methanol indichloromethane elution gave 20 mg of the yellow solid, 80%.

Compound 213, 217 was physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 59.

TABLE 59 Cd. Amine Structure IUPAC Name [M + H]⁺ 213 trans-4-aminocyclohexanol

trans-4-(3-(7- methoxythieno[3,2- c]pyridin-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 396.1 217 trans-4-methoxycyclohexana mine

trans-4- methoxycyclohexyl)- 3-(7- methoxythieno[3,2- c]pyridin-2-yl)imidazo[1,2- b]pyridazin-6-amine 410.5

Example 60 Synthesis of Compound 215

Preparation of4,5,6,7-tetrahydro-7-methylene-5-tosylthieno[3,2-c]pyridine

To a solution of methyltriphenylphosphonium bromide (2.05 g, 5.73 mmol,2.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (3.58 mL, 1.6 Msolution, 2.0 equiv) and stirred for 30 min followed by addition of5,6-dihydro-5-tosylthieno[3,2-c]pyridin-7(4H)-one (880 mg, 2.86 mmol,1.0 equiv) in THF (5.00 mL). The reaction mixture was stirred at rt for1 h, then quenched by the addition of a saturated aqueous solution ofammonium chloride. Purification by column chromatography using 5% ethylacetate in hexanes elution gave 175 mg of the yellow solid, 20%.

Preparation of 7-methylthieno[3,2-c]pyridine

To a solution of4,5,6,7-tetrahydro-7-methylene-5-tosylthieno[3,2-c]pyridine (150 mg,0.491 mmol, 1.0 equiv) in HOt-Bu (5 mL) was added KOt-Bu (110 mg, 0.982mmol, 2.0 equiv) and heated to reflux for 3 h. Purification by columnchromatography using ethyl acetate elution gave 62 mg of the yellowsolid, 85%.

Preparation of 7-methylthieno[3,2-c]pyridin-2-yl-2-boronic acid

To a solution of 7-methylthieno[3,2-c]pyridine (82 mg, 0.550 mmol, 1.0equiv) in THF (5.0 mL) at −78° C. was added n-BuLi (0.52 mL, 0.824 mmol,1.5 equiv). The reaction was stirred at the reduced temperature for 1 h,then triisopropylborate (0.19 mL, 0.824 mmol, 1.5 equiv) was added andstirred at rt for 2 h. The mixture was quenched with 2N HCl and thenextracted with ethyl acetate. Purification by column chromatographyusing 2% methanol in dichloromethane elution gave 80 mg of white solid,75%.

Preparation of6-chloro-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

To a solution of 7-methylthieno[3,2-c]pyridin-2-yl-2-boronic acid (71mg, 0.368 mmol, 1.0 equiv) in acetonitrile (3.68 mL) was added6-chloro-3-iodoimidazo[1,2-b]pyridazine (103 mg, 0.368 mmol, 1.0 equiv),palladium catalyst (27 mg, 0.0368 mmol, 0.1 equiv) and sodium carbonate(3.68 mL, 1.0 M, 10.0 equiv). The solution was stirred in the microwaveat 150° C. for 10 min. Purification using column chromatography gave 60mg of the yellow product, 54%.

Preparation ofN-(3,4-dimethoxyphenyl)-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine

To a solution of6-chloro-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(31 mg, 0.103 mmol, 1.0 equiv), xantphos (12 mg, 0.0206 mmol, 0.2equiv), palladium acetate (2 mg, 0.0103 mmol, 0.1 equiv), and potassiumcarbonate (284 mg, 2.06 mmol, 20 equiv) in dioxane (5.0 mL) was added3,4-dimethoxyaniline (24 mg, 0.155 mmol, 1.5 equiv) and heated to 110°C. for 2 h. Purification by column chromatography using 2% methanol indichloromethane elution gave 20 mg, of the brown solid, 47%.

Compound 214 was physically characterized by electrospray ionizationmass spectrometry. Structures and molecular masses are given below inTable 60.

Cd. Structure IUPAC Name [M + H]⁺ 214

N-(3,4-dimethoxyphenyl)-3- (7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin- 6-amine 418.0

Example 61 Synthesis of Compound 215, 216

Preparation ofN-alkyl-4-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol

To a solution of6-chloro-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(20 mg, 0.0665 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluenesulfonic acid monohydrate (13 mg, 0.0665 mmol, 1.0 equiv) and amine (38mg, 0.333 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reactionmixture was diluted with water and extracted with ethyl acetate.Purification by column chromatography using 5% methanol indichloromethane elution gave 22 mg of the yellow solid, 87%.

Compound 215, 216 was physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 61.

TABLE 61 Cd. Structure IUPAC Name [M + H]⁺ 215

trans-4-(3-(7- methylthieno[3,2- c]pyridin-2- yl)imidazo[1,2-b]pyridazin-6- ylamino)cyclohexanol 380.5 216

trans-4- methoxycyclohexyl)-3-(7- methylthieno[3,2- c]pyridin-2-yl)imidazo[1,2- b]pyridazin-6-amine 394.5

Example 62 Synthesis of Compounds 220, 221

Preparation ofN-((1r,4r)-4-methoxycyclohexyl)-N-methyl-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amineandtrans-4-(N-methyl-N-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol

To a solution oftrans-4-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol(37 mg, 0.0975 mmol, 1.0 equiv) in DMF (2.00 mL) was added sodiumhydride (20 mg, 0.488 mmol, 5.0 equiv) and methyl iodide (68 mg, 0.488mmol, 5.0 equiv). After 2 h, the reaction mixture was quenched withwater and extracted with ethyl acetate. Purification by columnchromatography gave 20 mg (50%) ofN-((1r,4r)-4-methoxycyclohexyl)-N-methyl-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amineas the less polar product and 10 mg (25%) oftrans-4-(N-methyl-N-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanolas the more polar product.

Compounds 220 and 221 were physically characterized by electrosprayionization mass spectrometry. Structures and molecular masses are givenbelow in Table 62.

TABLE 62 Cd. Structure IUPAC Name [M + H]⁺ 220

N-((1r,4r)-4- methoxycyclohexyl)-N- methyl-3-(7-methylthieno[3,2-c]pyridin- 2-yl)imidazo[1,2- b]pyridazin-6-amine 407.5221

trans-4-(N-methyl-N-(3-(7- methylthieno[3,2-c]pyridin- 2-yl)imidazo[1,2-b]pyridazin-6- yl)amino)cyclohexanol 394.5

Biochemical Assay

Biochemical Assay for the Inhibition of Kinase Activity for MLK-3:

Myelin basic protein (20 μM final concentration) is dissolved in 20 mMHepes (pH 7.5) containing 10 μM MgCl₂, 1 μM EGTA, 0.02% Brij35, 0.02mg/ml BSA, 0.1 μM Na₃VO₄, 2 mM DTT, and 1% DMSO. Activated MLK-3 isadded and mixed (20 nM final concentration), and inhibitors are added inDMSO. ³³P-ATP (specific activity 500 μCi/μL) is delivered into thereaction mixture to initiate the reaction (ATP concentration is 50 μM)and the mixture is incubated at room temperature for 20 minutes. %Activity is determined using a proprietary HOTSPOT™ microfluidic filterbinding technology. See, Expert Opin. Drug Discov. 2008 June; 3(6):607-621.

Reported MLK-3 Activity

Activity data for selected MLK-3 inhibitors is displayed in Table 63.The IC₅₀ MLK-3 range is denoted as follows: + denotes activity <5 μM, ++denotes activity between 0.5 μM to 1 μM, and +++ denotes activitybetween 0.1 μM to 0.5 μM, and ++++ denotes activity <0.10 μM.

TABLE 63 IC₅₀ MLK-3 COMPOUND # (μM) 3 +++ 4 +++ 5 ++++ 9 + 11 + 12 +++13 + 14 ++ 24 +++ 25 ++ 26 +++ 27 +++ 28 + 30 + 31 + 34 + 39 + 40 + 41++ 43 ++ 44 ++ 45 + 50 +++ 53 ++ 54 + 56 ++ 61 + 62 + 63 +++ 67 ++++ 68++++ 69 ++++ 70 ++++ 71 ++++ 72 +++ 73 ++ 74 ++ 75 +++ 76 + 77 ++++ 78+++ 79 ++++ 80 +++ 81 ++ 83 + 84 + 85 ++++ 86 +++ 87 ++++ 88 +++ 90 ++101 + 102 + 105 +++ 107 + 108 ++ 109 +++ 110 +++ 111 + 119 + 122 +++126 + 127 + 131 + 132 ++ 135 +++ 136 + 138 +++ 139 +++ 140 + 142 + 150 +158 + 160 ++ 161 +++ 162 ++ 163 ++ 164 ++ 166 ++ 167 +++ 168 +++ 169++++ 170 ++++ 171 ++++ 172 +++ 173 ++++ 174 ++++ 175 ++++ 176 +++ 177++++ 178 +++ 179 ++++ 180 + 181 +++ 182 + 183 + 184 + 185 + 186 +++ 187++ 188 + 189 + 190 + 191 + 192 ++ 193 + 194 + 195 + 196 +++ 197 +++198 + 199 + 200 ++ 201 +++ 202 + 203 +++ 204 +++ 205 +++ 206 ++++ 207+++ 208 + 209 ++ 210 + 211 + 212 + 213 ++++ 214 +++ 215 ++++ 216 +++ 217+++ 218 ++++ 219 + 220 +++ 221 +++

Blood Brain Barrier Penetration

Compounds disclosed herein may be evaluated in pharmacokinetic assaysand models to determine absorption, distribution, metabolism, andexcretion parameters. The choice and tailoring of in vitro and ex vivoassays and in vivo models will vary according to the route ofadministration/formulation, indication under study, properties of testcompounds, etc., as well as according to such factors as costs,availability of technology and resources, etc. Such parameters are wellknown in the fields of pharmacology and drug development. It is withinthe capacity of one skilled in the art to design and carry out, suchwork, or to outsource it to a capable third party.

Several compounds disclosed herein were evaluated in a standard murinepharmacokinetic model. Compounds were selected that exhibited reasonablesolubility and metabolic stability, and good predicted blood brainbarrier penetration, based on low molecular weight, a low number ofhydrogen bond donors, log D within a range of from 2 to 5, and low polarsurface area. For ease of analysis compounds were dissolved in 5% DMSO,40% PEG400, and 55% to yield a nominal concentration of 2 mg/mL forintravenous administration. Compounds were administered via a singleintravenous (IV) injection in CL57 BL/6 mice at 10 mg/kg inDMSO/PEG400/Saline solution. Three mice in each group were used forblood and brain collection at each time point. Blood samples (300 μL)were collected via the retro-orbital vein predose and at 30, 60 and 180minutes postdose. Blood samples were placed into tubes containing sodiumheparin and centrifuged under refrigerated conditions at 8000 rpm for 6minutes to separate plasma from the samples. The brain of each animalwas collected after the final blood collection. The whole tissue washarvested, excised and rinsed by saline, dried by filter paper, and thenplaced into one tube per tissue per animal. All samples were stored at−20° C. until bioanalysis. Compound concentrations in plasma and brainhomogenate were determined using a high performance liquidchromatography/mass spectrometry (HPLC/MS/MS) methods. Brainconcentrations at the three hour time point for several representativecompounds are disclosed below in Table 64.

TABLE 64 Compound # Cbrain 3 hrs (ng/g) URMC-099 950 (Positive Control)CEP-1347 67 12 1280 67 566 175 1880 68 1554

Protein Kinase Selectivity:

MLK-3 inhibitors previously reported in the literature are somewhatpromiscuous and inhibit a large number of serine and threonine proteinkinases. Compounds of the present invention that show potent inhibitionon MLK-3 are very specific for MLK family kinases. For comparison, IC₅₀values for selected compounds from the invention were compared against adiverse set of kinases for inhibition of the MLK-3 potent, brainpenetrant compound, URMC-099, which is disclosed in Goodfellow, V. S.,et al. A CNS Active, Orally Bioavailable Inhibitor of Mixed LineageKinase 3 for Potential Treatment of HIV Associated NeurocognitiveDisorder. Journal of Medicinal Chemistry, 2013.

TABLE 51 Compounds Kinase/Assay URMC-099 105 12 169 67 68 170ABL1(T315I) 3 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 CDK2 11801028 19,400 8,260 >10,000 >10,000 >10,000 IKKa591 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 IKKb257 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 IR200 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000

Neuroprotection from HIV-1 Tat:

E18 primary hippocampal neurons were plated in microfluidic chambers for7 days in vitro (DIV). These chambers contain a cell body compartmentcontiguous with a series of 10 um wide, 3 um high, 400 um longmicrogrooves through which axons grow into a second compartment,fluidically isolated by a hydrostatic pressure gradient. BV-2 microglialcells treated with 1 μg/ml HIV-1 Tat±test compounds (100 nM) wereintroduced into the second compartment for 18 hours. Chambers that wereexposed to BV-2 microglia treated with Tat alone had almost their entireaxonal field destroyed (FIG. 1, brightfield image). Treatment withvarious example compounds or URMC-099 protected the axon field. Thespecific MLK3 inhibitor, compound 68, promoted continued axonogenesis inthe presence of Tat-activated microglia (FIG. 1, arrows). FIGS. 2 and 3show quantifications of axon elimination in the presence of HIV tat andCompounds 169, 67, 68 and 175. (U=Control Inhibitor URMC-099, previouslyshown to protect against effects of HIV-Tat in vitro and in vivo.)

Western Blots of ICAM-5 Cleavage (FIG. 4):

Rat hippocampal neurons were dissected from E18 embryos and plated on96-well plates in Neurobasal medium supplemented with B27 plusantioxidants (AO) for 24 hours and then maintained in Neurobasalsupplemented with B27 minus AO for 12-14 days in vitro before use.Neurons were treated with vehicle or 20 mM of the non-competitiveN-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) orincreasing doses ranging between 10-300 nM of Compound 68 in 100 ml ofmodified Locke's buffer (no Mg²⁺) for 20 minutes before adding 10 or 100mM NMDA for 15 minutes. After NMDA treatment, the modified Locke'sBuffer was replaced with Neurobasal Medium supplemented with B27 minusAO and returned to a 37° C. incubator with 5% CO₂ overnight. The treatedneurons were washed with ice-cold PBS and fixed in 4% PFA+4% Sucrose for15 minutes and then washed 3 times with PBS. The fixed neurons were thenimmunostained with rabbit anti-ICAM-5 polyclonal antibody and a specificfluorescent secondary antibody for Odyssey System gel imaging fromLicor. Results are from 3 independent experimental replicates. In thisparadigm, neurotoxicity was measured as the amount of cleaved (i.e.,soluble) ICAM-5 that was released after excitotoxic injury fromsublethal doses of NMDA (Guo H, Tong N, Turner T, Epstein L G, McDermottM P, Kilgannon P, Gelbard H A. Release of the neuronal glycoproteinICAM-5 in serum after hypoxic-ischemic injury. Ann Neurol. 2000 October;48(4):590-602. PMID: 11026442; Conant K, Wang Y, Szklarczyk A, Dudak A,Mattson M P, Lim S T. Matrix metalloproteinase-dependent shedding ofintercellular adhesion molecule-5 occurs with long-term potentiation.Neuroscience. 2010 Mar. 17; 166(2):508-21. doi:10.1016/j.neuroscience.2009.12.061. Epub 2010 Jan. 4. PMID: 20045450).

Synaptodendritic Beading (FIG. 5):

Rat hippocampal neurons were dissected from E18 embryos and plated on 12mm glass coverslips in Neurobasal medium supplemented with B27 plusantioxidants (AO) for 24 hours and then maintained in Neurobasalsupplemented with B27 minus AO for 12-14 days in vitro (DIV) before use.Neurons cultured for DIV 12-14 were transfected with pMAX-GFP for 12hours and then treated with vehicle or 20 mM MK-801 and 200 nM ofCompound 68 in 0.5 ml of modified Locke's buffer (no Mg²⁺) for 20minutes before adding 10 mM NMDA for <5 minutes. After NMDA treatment,the neurons were washed with ice-cold PBS and fixed in 4% PFA+4% Sucrosefor 15 Minutes and then washed 3 times with PBS. The beaded and unbeadedneurons were identified by GFP expression and quantitated per 20× fieldusing fluorescence microscopy. Results are from three independentexperimental replicates. In this paradigm, neurotoxicity is defined asthe extent of synaptodendritic beading in each microscopic field(Bellizzi M J, Lu S M, Masliah E, Gelbard H A. Synaptic activity becomesexcitotoxic in neurons exposed to elevated levels of platelet-activatingfactor. J Clin Invest. 2005 November; 115(11):3185-92. PMID: 16276420).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described herein.

All applications, publications, patents and other references citedherein are incorporated by reference in their entirety. In case ofconflict, the specification, including definitions, will control. Asused herein, the singular forms “a”, “and,” and “the” include pluralreferents unless the context clearly indicates otherwise. Thus, forexample, reference to “a peptide sequence” or a “treatment,” includes aplurality of such sequences, treatments, and so forth.

The invention is generally disclosed herein using affirmative languageto describe the numerous embodiments. The invention also specificallyincludes embodiments in which particular subject matter is excluded, infull or in part, such as substances or materials, method steps andconditions, protocols, procedures, assays or analysis. Thus, even thoughthe invention is generally not expressed herein in terms of what theinvention does not include, aspects that are not expressly included inthe invention are nevertheless disclosed herein.

Where features or aspects of the invention are described in terms ofMarkush groups, those skilled in the art will recognize that theinvention is also thereby described in terms of any individual member orsubgroup of members of the Markush group. For example, if X is describedas selected from the group consisting of A, B, C, claims for X being Aand claims for X being B and C are fully described. Moreover, wherefeatures or aspects of the invention are described in terms of Markushgroups, those skilled in the art will recognize that the invention isalso thereby described in terms of any combination of individual membersor subgroups of members of Markush groups. Thus, for example, if X isdescribed as selected from the group consisting of A, B, and C, and Y isdescribed as selected from the group consisting of D, E, and F, claimsfor X being A and Y being D are fully described.

We claim:
 1. A method for treating a MLK-mediated disease comprisingadministering to a subject a therapeutically effective amount of apharmaceutical composition comprising a compound having the structure ofFormula I

or a pharmaceutically acceptable isomer, isotope, enantiomer, salt,ester, prodrug, hydrate or solvate thereof, wherein J has a structure of

where J is optionally substituted with up to four R₁₀, each R₁₀ isindependently selected from the group consisting of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR₆; X is NR₁₂ or S; each X₁,X₂, X₃, and X₄ is independently CH or N and wherein no more than one ofX₁, X₂, X₃, and X₄ is N; Y is —W—(CH₂)_(n)—R₁,

W is null, phenylene, or —NR₆-phenylene, where the NR₆ is attached tothe imidazopyridazine core structure of Formula I; R₁ is —NR₂R₃, orpiperazinyl, where the nitrogen atom of the piperazinyl is optionallysubstituted with alkyl or alkoxy; R₂ is H or alkyl; R₃ is selected fromthe group consisting of C₂-C₁₀ alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, where any atom of R₃ is optionally substituted withone or more R₇; or R₂ and R₃ taken together with the N atom to whichthey are attached form a 3- to 7-membered heterocyclic ring optionallysubstituted with R₈; R₄ is H or alkyl; R₅ is H, alkyl, or NHR₉; R₆ is Hor alkyl; each R₇ is independently alkyl, cycloalkyl, alkoxy,cycloalkoxy, cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH,hydroxyalkyl, —COOR₁₁, or —O—(CH₂)_(m)—OH; R₈ is alkoxy, hydroxyalkyl,or COOR₁₁; R₉ is H, alkyl, or cycloalkyl; R₁₁ is H, or alkyl; R₁₂ is H,or alkyl; n is 0 or 1; m is 1, 2, or 3; and p is 1, 2, or 3; with theproviso that if J is an unsubstituted benzothiophene, then R₃ is eitheraryl or heteroaryl, where any atom of R₃ is optionally substituted withone or more R₇; and together with at least one pharmaceuticallyacceptable carrier, diluent or excipient.
 2. The method of claim 1wherein J is selected from the group consisting of


3. The method of claim 1 wherein J is

wherein each R₁₀ is independently selected from the group consisting ofF, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH₃;and k is 0, 1, 2, or
 3. 4. The method of claim 1 wherein J is

wherein each R₁₀ is independently selected from the group consisting ofF, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH₃;and k is 0, 1, 2, or
 3. 5. The method of claim 4 wherein each of X₁, X₂,X₃, and X₄ is CH.
 6. The method of claim 4 wherein X₁ is N, and each ofX₂, X₃, and X₄ is CH.
 7. The method of claim 4 wherein X₂ is N, and eachof X₁, X₃, and X₄ is CH.
 8. The method of claim 4 wherein X₃ is N, andeach of X₁, X₂, and X₄ is CH.
 9. The method of claim 4 wherein X₄ is N,and each of X₁, X₂, and X₃ is CH.
 10. The method of claim 1 wherein Y is—W—(CH₂)_(n)—R₁.
 11. The method of claim 10 wherein R₁ is —NR₂R₃. 12.The method of claim 11 wherein R₃ is selected from the group consistingof C₂-C₁₀ alkyl, aryl, and cycloalkyl.
 13. The method of claim 12wherein R₃ is phenyl optionally substituted with one or more R₇, whereineach R₇ is independently selected from the group consisting of hydroxyl,methoxy, —COOH, —O—(CH₂)_(m)—OH, cyclopropylmethoxy, cyclopentylmethoxy,and isopropyl.
 14. The method of claim 13 wherein each R₇ isindependently selected from the group consisting of methoxy, —COOH, and—O—(CH₂)₃—OH.
 15. The method of claim 11 wherein R₃ is C₂-C₁₀ alkyl,aryl, and cycloalkyl, where any atom of R₃ is optionally substitutedwith one or more R₇.
 16. The method of claim 1 wherein the compound isselected from any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer, orisotope thereof.
 17. The method of claim 16 wherein the compound isselected from any of

or any pharmaceutically acceptable salt, tautomer, stereoisomer, orisotope thereof.
 18. A method of claim 1, wherein the compound isselected from any of compounds shown below: Compound # Structure 3

4

5

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19. The method of claim 1, wherein the subject is a human being.
 20. Themethod of claim 1, wherein the MLK-mediated disease is selected from thegroup consisting of stroke, diabetes mellitus, hyperglycemia,retinopathy, nephropathy, neuropathy, ulcers, microangiopathies,macroangiopathies, gout, diabetic foot disease, insulin resistance,metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia,obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis,peripheral inflammation, cancer, hepatitis, steatohepatitis, HIVassociated neurocognitive disorder, HIV associated neuropathy,Alzheimer's disease, Parkinson's disease, multiple sclerosis,neurodegenerative disease, cirrhotic liver disease, and cirrhoticpancreatic disease.
 21. A method for treating a MLK-mediated diseasecomprising administering to a subject a therapeutically effective amountof a pharmaceutical composition comprising a compound having thestructure of Formula I

or a pharmaceutically acceptable isomer, isotope, enantiomer, or saltthereof, wherein J has a structure of

substituted with up to four R₁₀, or J has a structure of

optionally substituted with up to four R₁₀, each R₁₀ is independentlyselected from the group consisting of halo, alkyl, haloalkyl, alkoxy,haloalkoxy, —OH, and —OCOR₆; X is NR₁₂ or S; one of X₁, X₂, X₃, and X₄is N and the other three of X₁, X₂, X₃, and X₄ are CH; Y is—W—(CH₂)_(n)—R₁,

W is null, phenylene, or —NR₆-phenylene, where the NR₆ is attached tothe imidazopyridazine core structure of Formula I; R₁ is —NR₂R₃, orpiperazinyl, where the nitrogen atom of the piperazinyl is optionallysubstituted with alkyl or alkoxy; R₂ is H or alkyl; R₃ is selected fromthe group consisting of C₂-C₁₀ alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, where any atom of R₃ is optionally substituted withone or more R₇; or R₂ and R₃ taken together with the N atom to whichthey are attached form a 3- to 7-membered heterocyclic ring optionallysubstituted with R₈; R₄ is H or alkyl; R₅ is H, alkyl, or NHR₉; R₆ is Hor alkyl; each R₇ is independently alkyl, cycloalkyl, alkoxy,cycloalkoxy, cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH,hydroxyalkyl, —COOR₁₁, or —O—(CH₂)_(m)—OH; R₈ is alkoxy, hydroxyalkyl,or COOR₁₁; R₉ is H, alkyl, or cycloalkyl; R₁₁ is H, or alkyl; R₁₂ is H,or alkyl; n is 0 or 1; m is 1, 2, or 3; and p is 1, 2, or 3; with theproviso that if J is an unsubstituted benzothiophene, then R₃ is eitheraryl or heteroaryl, where any atom of R₃ is optionally substituted withone or more R₇.